While we have never been as spoiled for treatment choice as we are now, PI3K inhibitor safety is being very closely monitored by the FDA.
So, it's timely that Sigrid S Skanland and Jennifer R Brown have written a peer-reviewed Haematologica early view paper that discusses "the current status of PI3K inhibitors in CLL, factors limiting the use of currently approved PI3K inhibitors in CLL, current strategies to overcome these limitations, and where to go next."
"Phosphatidylinositol 3-kinase (PI3K) inhibitors are effective in chronic lymphocytic leukemia (CLL). However, the severe toxicity profile associated with the first-generation inhibitors idelalisib and duvelisib, combined with the availability of other more tolerable agents, have limited their use."
Not all of us do well on a BTKi drug or venetoclax but we may do brilliantly on a PI3K drug, provided the risk is acceptable. If we've exhausted approved treatments there's a reasonable risk gap between PI3K inhibitors and some of the more experimental treatments, which can also be much harder to access than an oral (tablet) medication. Additionally, some with severe renal or heart disease or significant risk of tumor lysis might be well served by treatment with a PI3K inhibitor.
"It is therefore of interest to optimize the administration of currently approved PI3K inhibitors and to develop next-generation agents to improve tolerability, so that this class of agents will be considered an effective and safe treatment option when needed."
"Optimizing their use by developing more specific next-generation inhibitors, reducing toxicity and defining the ideal sequence or combination of therapies are therefore necessary to further improve CLL outcomes."
"Current strategies to overcome treatment limitations include intermittent dosing, which is established for copanlisib and zandelisib and under investigation for duvelisib and parsaclisib. A second strategy is to combine the PI3K inhibitor with another novel agent, either as a continuous regimen or a fixed-duration regimen, to deepen responses."
The authors note that 'there are a large number of emerging clinical trials with PI3K inhibitors in CLL'.
'Although the implementation of PI3K inhibitor-based regimens in CLL management has faced various challenges, efforts remain high to optimize its use and identify tolerable schedules and combinations. Both patient selection and optimized patient management can reduce risk. . . . Importantly also, new clinical trial designs better reflect current recommendations by including patients who have been exposed to several lines of therapy, including targeted therapies and in some cases even a PI3K inhibitor.'
The authors conclude by explaining ways to facilitate precision medicine that will "maximise efficacy and minimise toxicity by matching the right therapy to the right patient at the right time". These measures include:
"Higher-resolution patient stratification made possible if biomarkers identified in pre-clinical studies can be validated in biomarker-driven clinical trials and implemented in routine practice . . . clinical trials of novel therapies should biobank samples dedicated to functional analyses such as cell signalling profiling, immune phenotypes, and ex vivo drug sensitivity testing, in addition to genetic profiling, to allow for the identification of molecular signatures predictive of treatment responses including tolerability. To develop truly predictive prognostic markers in this heterogeneous disease, sharing of comprehensive clinical, genetic, and functional data from both clinical trials and real-world cohorts is necessary. Based on these data, maximally predictive models and minimal biomarker signatures can be developed to inform personalised treatment decisions. This approach to precision medicine is exemplified in the EU funded CLL-CLUE consortium."
Sigrid S. Skanland, Jennifer R. Brown, 'PI3K inhibitors in chronic lymphocytic leukemia: where do we go from here?' Haematologica, 2022 July 28, doi.org/10.3324/haematol.20... [epub ahead of print]
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The FDA seems eager to withdraw approval of duvelisib and has make it even harder, slower and more expensive for all new CLL drug to get to market in USA. While we very much appreciate that they are looking out for our safety, we hope the data will convince them that despite their really significant toxicity, PI3Ki still have a critical role to play for some with CLL, especially double exposed patients. If you live in the US and have been helped by a PI3Ki, especially duvelisib, please message or email me about speaking or submitting a note to the FDA at their upcoming review. Thanks.
Some encouraging news in the story of PI3K inhibitors appeared in a research article dated 23 August 2022 in the journal "Clinical Cancer Research". Titled "Functional testing to characterize and stratify PI3K inhibitor responses in chronic lymphocytic leukemia", it demonstrates that functional testing can predict response to PI3K inhibitors in CLL patients. (my emphasis)
The study "characterized the activity and cellular effects of ten PI3Ki and investigated whether functional analyses can identify treatment vulnerabilities in PI3Ki-refractory/intolerant CLL and stratify responders to PI3Ki."
It found that "pan-PI3Ki were most effective at inhibiting PI3K signaling and cell viability, and showed activity in CLL cells from both treatment-naïve and idelalisib-refractory/intolerant patients. CLL cells from idelalisib-refractory/intolerant patients showed overall reduced protein phosphorylation levels. The pan-PI3Ki copanlisib, but not the p110d inhibitor idelalisib, inhibited PI3K signaling in CD4+ and CD8+ T cells in addition to CD19+ B cells, but did not significantly affect T cell numbers. Combination treatment with a PI3Ki and venetoclax resulted in synergistic induction of apoptosis. Analysis of drug sensitivities to 73 drug combinations and profiling of 31 proteins stratified responders to idelalisib and umbralisib, respectively."
The findings "suggest novel treatment vulnerabilities in idelalisib-refractory/intolerant CLL, and indicate that ex vivo functional profiling may stratify PI3Ki responders."
Yanping Yin, Paschalis Athanasiadis, Linda Karlsen, Aleksandra Urban, Haifeng Xu, Ishwarya Murali, Stacey M. Fernandes, Alberto J. Arribas, Abdul K. Hilli, Kjetil Taskén, Francesco Bertoni, Anthony R. Mato, Emmanuel Normant, Jennifer R. Brown, Geir E. Tjønnfjord, Tero Aittokallio, Sigrid S. Skånland; Functional testing to characterize and stratify PI3K inhibitor responses in chronic lymphocytic leukemia. Clin Cancer Res 2022; doi.org/10.1158/1078-0432.C...
As already noted by bkoffman in his earlier reply to this post, the FDA is considering withdrawing approval for duvelisib as an additional treatment option for relapsed/refractory CLL.
Now, the CLL Society is asking CLL patients to "please consider submitting a personal comment to the FDA".
" . . . if the FDA hears from multiple patients on this issue, there may be a higher chance of significantly moving the needle."
"It doesn’t matter if you have or have not been on duvelisib before! As a patient, you can talk about the sincere need to have further treatment options available to you in the future should the only other two FDA-approved drug classes fail you."
". . . patients who run out of therapy options when their disease progresses after being on both a BTK and a BCL-2 inhibitor have a dismal prognosis. Therefore, continuing to have PI3K inhibitors as a remaining FDA-approved treatment option is extremely important."
"There are risks involved with any drug, and we do not want to downplay the potential toxicities associated with PI3K inhibitors. We also acknowledge that duvelisib is far from being a perfect medication. However, we disagree with the FDA'S conclusions. We believe that the decision to take duvelisib should be a continued available treatment option as part of the shared decision-making process between a patient and their healthcare provider as to whether it is an appropriate choice."
"On September 23, 2022, the Oncologic Drug Advisory Committee (ODAC) will review the drug's previous approved use "for treating adult patients with relapsed or refractory CLL/SLL after having been on at least two prior therapies." September 8 is the date that really matters, as this is the deadline to submit your personal comments to be reviewed by ODAC."
For further details and information about ways to lodge your personal statement, visit the CLL Society's website: cllsociety.org/2022/08/we-n...
The FDA's Oncologic Drugs Advisory Committee (ODAC) has voted against Duvelisib for relapsed or refractory chronic lymphocytic leukemia
"In an 8 to 4 vote, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted that the final overall survival (OS) data submitted did not demonstrate a strong enough benefit-risk ratio to support the continued approval of duvelisib (Copiktra) for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least 2 prior therapies."
The FDA's Oncologic Drugs Advisory Committee (ODAC) made a clean sweep of its 2-day meeting, deciding that the PI3K inhibitor duvelisib (Copiktra) does not offer a favorable risk-benefit ratio for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
By an 8-4 vote, the panel came down on the side of the FDA staff perspective that duvelisib had a potentially detrimental effect on survival in a randomized trial that supported Secura Bio's approval application. Analysis of 5-year overall survival (OS) from the randomized DUO trial showed a hazard ratio of 1.09 versus the ofatumumab (Arzerra) control arm in an intention-to-treat analysis and 1.06 in the indicated population (relapsed/refractory disease and two or more prior lines of therapy).
Adjusted analyses yielded similar results. Although not statistically significant, the suggestion of a survival detriment, along with evidence of high rates of toxicity, swayed the panel's overall opinion.
"If you have an indolent disease, and overall survival obviously is very difficult to figure out in that setting, then you become more compelled by the overall response rate and progression-free survival," said Christopher Lieu, MD, of the University of Colorado Cancer Center in Aurora. "The progression-free survival benefit here is compelling ... and we want more drugs in this setting."
"If you have a disease where survival is measured in weeks to months, the bar you set for toxicity and what you're expecting out of the therapy is pretty low," he added. "But the flip side is also true. If you have an indolent disease, what is the cost to our patients that we're going to expect out of a therapy in a setting where we're not sure that it improves overall survival?"
:
Rocky History
Approved 4 years ago, duvelisib was hailed as "an important addition to the evolving treatment paradigm for patients with CLL/SLL and follicular lymphoma (FL)." In the phase III, multicenter, randomized DUO trial of CLL/SLL, patients who received the PI3K inhibitor had a 7-month improvement in median progression-free survival (PFS) versus ofatumumab and a two-fold improvement in objective response rate.
Duvelisib had more toxicity versus ofatumumab, but appeared to be less toxic than idelalisib (Zydelig), the first approved drug in the PI3K inhibitor class. OS data, a secondary endpoint in DUO, were immature at the time of the approval.
The FL approval was based on the phase II single-arm DYNAMO trial, which showed a 43% response rate in rituximab (Rituxan)-refractory patients. The accelerated approval came with the stipulation that the sponsor (at the time, Verastem) would conduct a confirmatory trial.
Hopefully they don’t crush the class of drugs. It sounds like intermittent therapy with some PI3Ks turns out to be the approach to buy a patient some time.
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Alterations of the immune system caused by CLL B‐cells 
