New York City NYC view Photo Credit: Sally ChurchThis week I’m attending an interesting 2-day conference on PI3K at the New York Academy of Sciences (NYAS).

It brings together a broad faculty of researchers in the field looking at novel aspects of the PI3K-Akt-mTOR pathway in depth.

One aspect that has become clear with these compounds is that there’s probably more that we don’t know than we do – it’s a highly complex network of nodes and cause-effect that needs to be unravelled.

We do know a few things though, for example, PI3K and mTOR are often activated in advanced disease and can cause resistance to therapy as we have seen with aromatase inhibitors in ER+ disease and trastuzumab in HER2+ breast cancer.  We also know that inhibiting PI3K or mTOR can lead to activation of compensatory pathways that serve to drive oncogenic signalling and tumour survival.  It’s complicated!

The most advanced agent in the PI3K class is probably Gilead/Calistoga’s GS-1101 (formerly CAL-101), which is a delta isomer inhibitor being evaluated in B-cell hematologic malignancies such as mantle cell lymphomas (MCL), indolent NHL and CLL.  After promising phase I and II trials, it has now moved into randomised controlled phase III trials.

Yesterday, Langdon Miller (Gilead) gave a nice overview of the GS-1101 program. One couldn’t help but marvel at the waterfall plots obtained to date, along with the before and after pictures of a women in her 40’s with refractory CLL – a dramatic difference – she looked like a completely different person!  Of course, there are a number of questions that need to be addressed next:

  • Is survival prolonged in heavily refractory patients accustomed to immunotherapy?
  • How reproducible and durable are these responses on a large scale?
  • How can the redistribution of the lymphocytes be addressed?  Will chemotherapy help here?
  • Is there value in combining a PI3Ki with immunotherapy in earlier stage disease?

All of these questions are being evaluated in the next phase of the GS-1101 clinical trials.  I was impressed with the progress and where Gilead are going with the compound.

There are some questions that remain in my mind though.  CLL and iNHL have an embarrassment of riches in pipeline agents at the moment, with several promising compounds in development.

The obvious rival to PI3K delta inhibitors are the bruton kinase inhibitors (BTK) such as Pharmacyclics/J&J’s ibrutinib (PCI-32765), which reported impressive data at ASH last December, followed up by new data at ASCO on the combination of ibrutinib with an approved CD20 antibody, ofatumumab.

This got me thinking…

1) If we assume that both agents are lucky enough to get approved by the FDA sometime in the near future, how will oncologists and hematologists decide which agent to give which patient?  Can patients be stratified in any way in order to define selection for treatment?

2) Is there any data on whether combining these agents together would be synergistic? (I don’t think so, yet)

3) If a PI3K-delta and a BTK inhibitor were synergistic preclinically, what are the chances emerging of a combination trial between the four companies involved in the development of GS-1101 and ibrutinib?  Sadly, a cynic would shake their head and say very low, but we need an answer on 2) from academic research before we get too excited.

4) What are the mechanisms of adaptive resistance in patients to both classes of agents in CLL and NHL?  If we know the answer to this critical question, then rational combinations could be investigated further.

5) Would combining GS-1101 with CD20 antibody immunotherapies such as rituximab and ofatumumab be an interesting approach to see if better response rates and outcomes will be achieved?  These are indeed being planned, along with a combination with bendamustine, another drug often used in relapsed/refractory NHL and CLL.

6) How will sequencing be important?  If a patient is eligible for either therapy, which one should be tried first?  This area is rather murky right now.

We’ve come a long way so far with both of these compounds, but there’s still an even longer way to go before we have some clarity on how they might change clinical practice and help improve outcomes for patients with NHL and CLL.

This is definitely an exciting area to watch out for, even if we have more questions than answers right now.