The future of phosphatidylinositol 3-kinase (PI3K) inhibitors in the treatment of hematologic malignancies is murky at best, and what that means for patients with chronic lymphocytic leukemia (CLL) is unclear.
Two PI3K inhibitors approved by the U.S. Food and Drug Administration (FDA) remain on the market for relapsed or refractory (R/R) CLL: idelalisib in combination with rituximab and duvelisib.1
“I treat a lot of patients with CLL, and every once in a while, I use this class of drugs if I am out of options,” said Mazyar Shadman, MD, MPH, associate professor at Fred Hutchinson Cancer Center and University of Washington School of Medicine in Seattle. “So, do I use it? Yes. Is it the best option? No. I often use it as a short bridge to something else.”
Dr. Shadman said, however, that if he had been asked a year ago whether this class of drug had a future in CLL, he likely would have answered differently. He would have felt hopeful, but a lot has changed since then.
In early 2022, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 16-0 with one abstention to recommend that future approvals of PI3K inhibitors for hematologic malignancy indications be supported by randomized trial data. This decision was supported by data indicating a class-specific excess of fatal adverse events (AEs) and high rates of toxicity.2
“We want a drug to work but must make sure it’s not causing harm,” Dr. Shadman said. “I understand the FDA’s decision on this.”
ASH Clinical News recently spoke with Dr. Shadman and several other CLL clinicians about the rise of PI3K inhibitors as a drug class, what problems occurred leading to the FDA’s decision, and what lessons can be learned from its evolution.
PI3K Drug Class
Matthew S. Davids, MD, MMSc, director of clinical research in the Division of Lymphoma at Dana-Farber Cancer Institute in Boston, was just starting his career as a new faculty member when idelalisib was in its phase I clinical trials.
“I have been involved with this class of drug for almost 15 years at this point,” Dr. Davids said. “Early on, we recognized that PI3K inhibitors could interrupt one of the key pathways for survival for malignant B-cell lymphomas, which was the B-cell receptor signaling pathway.”
According to Dr. Davids, these early trials were showing dramatic response in patients with CLL who had exhausted all prior therapies and had very few other options. Around this same time, another new class of drugs, Bruton tyrosine kinase (BTK) inhibitors, was also entering early clinical trials.
Both drugs targeted different enzymes attempting to inhibit the growth and proliferation of CLL cells, and both were among the potential first targeted therapies for the disease.
In July 2014, the FDA granted accelerated approval to idelalisib plus rituximab for the treatment of CLL; the drug also received approval as a monotherapy for relapsed follicular lymphoma (FL) and small lymphocytic lymphoma (SLL).3 The CLL indication was based on a randomized phase III trial that showed a progression-free survival (PFS) benefit when idelalisib was added to rituximab compared with rituximab alone.
The approved idelalisib label included a boxed warning regarding the potential for fatal and serious toxic effects: enteritis, pneumonitis, and hepatitis.
Early Signs of AEs
“Within the first couple of years, as data from the early phase trials matured, we saw some signals of toxicity,” Dr. Davids said. “Liver inflammation, pneumonitis, colitis, infections … there was some hesitation around that.”
According to Joanna M. Rhodes, MD, MCSE, director of the lymphoma program at Rutgers Cancer Institute of New Jersey in New Brunswick, these toxicities could be managed, but the degree of management depended on early identification and liberal dose reductions or intermittent dosing.
Dr. Davids added that these toxicities were familiar to the academic investigators who had experience with idelalisib from clinical trials. Unfortunately, “as these drugs were approved and began to be used more widely, some patients in this real-world setting started to get into trouble with toxicities even more frequently than in the trials.”
According to the FDA, serious AEs occurred in as many as 65% of patients during trials, and grade 3 or worse AEs in as many as 85%.1
“As a consequence, a lot of patients had to reduce the drug dose or stop therapy all together, both in clinical trials and even more so outside of clinical trials,” said Sigrid Skånland, PhD, a researcher at the Institute for Cancer Research at Oslo University Hospital in Norway. “In clinical trials it was easier to monitor patients and correct for these side effects, but outside of trials they became more of a concern.”
In 2016, the FDA confirmed that Gilead had halted six randomized clinical trials of idelalisib in combination with standard therapy in firstline CLL and for relapsed indolent non-Hodgkin lymphoma (iNHL)/SLL when data showed an increased number of deaths related to infections in the idelalisib arms. A pooled analysis showed a combined percentage of deaths for idelalisib of 7.4% compared with 3.5% in the placebo arms.4
Dr. Shadman said clinicians learned early on that attempting to use idelalisib in the firstline setting increased many of the immune-mediated AEs seen in patients with R/R disease.
“These patients who were not previously exposed to chemotherapy — unlike in the R/R setting — have healthier immune systems and healthier T cells, leading to more T-cell mediated toxicities,” Dr. Shadman said.
Dr. Davids remembered being surprised by the rate of infections because that had not been his experience with idelalisib.
“These phase III trials did not, in some cases, incorporate mandatory antimicrobial prophylaxis for infections, and that may have contributed to the high rate of infections in the idelalisib arms,” Dr. Davids said. “The detriment to overall survival (OS) in the idelalisib arms was concerning, especially to the FDA, and appropriately led to those trials being shut down. That was a turning point.”
Concurrently to all of this, the BTK inhibitor ibrutinib received accelerated approval for R/R CLL in 2014.5
“Ibrutinib was picked up in the community much faster, and idelalisib became a second choice,” Dr. Shadman said. The black box warning and the trials being halted only added to skepticism about the PI3K inhibitor drug class.
Me Too Drug?
In 2018, the FDA approved another PI3K inhibitor, duvelisib, for R/R CLL or SLL based on the results of the DUO trial, which demonstrated a PFS advantage for duvelisib compared with ofatumumab (hazard ratio [HR] = 0.52; 95% CI 0.39-0.69; p<0.0001).1 At the time of approval, OS data were immature. Duvelisib was also approved with a black box warning of fatal or serious toxicities, including infections, diarrhea/colitis, cutaneous reactions, and pneumonitis.
“Even from the beginning, no one claimed duvelisib was cleaner or better tolerated; it was a ‘me too’ drug to many of us,” Dr. Shadman said. “The drug was developed using the same daily dosing with the same side effect profile. Duvelisib did not serve the class in terms of making it better tolerated.”
One benefit to duvelisib was that it was approved as a single agent and was an all-oral regimen in contrast to idelalisib plus rituximab. Despite that, the approval of duvelisib, in the absence of any effort for changing dosing or administration, did not change the reputation of the class.
Indeed, more research into dose optimization could have benefited these early PI3K inhibitors. A review by Dr. Skånland and Jennifer R. Brown, MD, PhD, director of the CLL Center of the Division of Hematologic Malignancies at Dana-Farber Cancer Institute, estimated that within clinical trials, dose reductions occurred in as many as 58% of patients assigned idelalisib, with as many as 39% of patients discontinuing drugs due to AEs. Outside of trials, it is likely that these rates were even greater.6
Dr. Davids said there was a lot of excitement around umbralisib, another PI3K inhibitor that appeared to have a different safety profile and seemed comparably efficacious as the other drugs in the class. Unlike idelalisib, which primarily blocked the delta isoform of PI3K, and duvelisib, which blocked the delta and gamma isoforms, umbralisib inhibited PI3K-delta and casein kinase-1-epsilon.
Umbralisib received FDA accelerated approval for R/R FL and marginal zone lymphoma (MZL) in 2021.7
However, a significant issue with umbralisib arose with the UNITY-CLL trial, according to Dr. Rhodes. UNITY-CLL compared umbralisib plus ublituximab, obinutuzumab plus chlorambucil, umbralisib monotherapy, and ublituximab monotherapy. The trial demonstrated a PFS benefit for umbralisib plus ublituximab compared with chemoimmunotherapy (HR=0.546; 95% CI 0.413-0.720; p<0.0001).8 An early assessment of OS, however, showed a 23% higher mortality among patients assigned to umbralisib plus ublituximab.
Shortly before the FDA’s April 2022 ODAC meeting to address PI3K inhibitors, umbralisib’s manufacturer, TG Therapeutics, withdrew its pending supplemental New Drug Application (NDA) from the FDA.9
“Umbralisib was a well-tolerated PI3K but was given in conjunction with ublituximab, an anti-CD20 monoclonal antibody, every three months in perpetuity,” Dr. Rhodes said. “In general, we normally stop maintenance rituximab in other B-cell malignancies, but with that persistent B-cell depletion, there were more deaths, many of which we eventually found out were related to COVID-19.”
Dr. Davids said that when the results of UNITY-CLL were presented at the 2021 American Society of Hematology Annual Meeting, there was excitement around it.
“Unfortunately, the study spanned the peak of the COVID-19 pandemic at a time when there were no treatments, no vaccines, and there ended up being a significant number of deaths due to infection and COVID,” Dr. Davids said. “Patients on the control arm got six months of chemotherapy before the pandemic and then were not being monitored on the study, whereas patients on umbralisib were on study and being monitored, and some got infections and died.”
These data “sank the ship,” Dr. Davids said. “We lost our potentially best PI3K inhibitor approval, and sadly, we had patients on the drug on trials and benefitting from it, and we had to take it away from them because the company no longer had a viable path toward FDA approval in CLL.”
ODAC’s Decision and Aftermath
The data out of UNITY-CLL prompted the FDA’s April 2022 ODAC meeting to discuss PI3K inhibitors as a drug class. Its decision to require randomized controlled data and randomized dose-optimization data led to withdrawal of applications for several indications and voluntary withdrawal of certain PI3K inhibitors from the market (see TABLE).
“Later in the game, a few companies looked at PI3K inhibitors and recognized that these were good drugs given at the wrong schedule,” Dr. Shadman said. “It should not be a fixed dose taken indefinitely. Instead, let’s modify the schedule, give the drug for a few months at the full dose, and then begin to lower the dose or decrease the frequency.”
One drug that Dr. Shadman had high hopes for was zandelisib, a PI3K inhibitor being studied on an intermittent schedule. Just before the April 2022 ODAC meeting, MEI Pharma announced it would not submit an application to the FDA based on its phase II TIDAL study and was encouraged by the FDA to continue its phase III COASTAL study. However, the company later announced it was discontinuing development of zandelisib outside of Japan.10,11
According to Dr. Skånland, newer clinical trials could have looked at different dosing regimens or schedules, but the FDA’s new requirements make those types of studies unlikely. “It is going to be hard to find investors to continue development of this drug class,” she said.
In Dr. Davids’ view, the reduced availability of these drugs is a lost opportunity for patients. He still has patients on duvelisib and finds it useful in certain situations.
Dr. Rhodes, however, said she is reaching for PI3K inhibitors less and less in clinical practice.
“To get expanded access to pirtobrutinib — a noncovalent BTK inhibitor — you needed to have patients who were penta-refractory, and that included PI3K inhibitors,” Dr. Rhodes said. “If pirtobrutinib is approved in CLL, the likelihood of using PI3K inhibitors decreases even further.”
Dr. Shadman agreed that any role for PI3K inhibitors is likely shrinking. He explained that early trials of PI3K inhibitors looked at later line therapy in the setting of prior use of chemotherapy. Today, though, patients moving to second- or third-line therapies are coming off of BTK inhibitors or venetoclax, not chemotherapy. Therefore, while considered a “later line option,” they are not relevant to patients in today’s practice.
“We don’t have efficacy data for PI3K inhibitors for patients coming off BTK inhibitors or BCL2 inhibitors,” Dr. Shadman said.
Even in later lines, the ASCEND trial tested acalabrutinib versus investigator’s choice of idelalisib plus rituximab or bendamustine plus rituximab and found that acalabrutinib was superior to both regimens used in the control arm.12
“Many patients discontinued idelalisib on that study, but in an intent-to-treat, head-to-head trial, intolerance of a drug and its contribution to efficacy is an important part of the question that is being asked,” Dr. Shadman said.
Lessons Learned
Dr. Davids said the FDA was acting from the right place in its decisions about PI3K inhibitors and more careful dose-finding studies would have been helpful for this drug class.
“A lot of academic investigators were advising pharma about how to design trials to develop safer ways to administer this class of drugs,” Dr. Davids said. “That advice was not always followed, and it is an example of how close partnership between companies and academic investigators is important.”
Dr. Rhodes said PI3K inhibitors are the “poster child” for a drug class that should have been looking for a minimum-effective dose instead of a maximum-tolerated dose.
“In my own clinical practice, the patients who stayed on these drugs the longest were on low doses intermittently,” Dr. Rhodes said. “I have patients who tolerated them for years this way.”
The “failure” of this drug class also demonstrates the importance of a better understanding of off-target effects, which tend to be more unpredictable than AEs seen with cytotoxic chemotherapy, Dr. Rhodes said.
With just two FDA-approved PI3K inhibitors remaining, the number of newer therapies for CLL is continuing to grow, and greater hope is being placed in cellular therapies, bispecific antibodies, or other mechanisms for targeting the B-cell receptor pathway, Dr. Rhodes said.
“I am not aware of any promising activity in the field that would tell me that PI3K inhibitors will be coming back,” Dr. Shadman said.
References
- U.S. Food and Drug Administration. FDA briefing document. Oncologic Drugs Advisory Committee meeting. April 21, 2022. Phosphatidylinositol 3-kinase (PI3K) inhibitors in hematologic malignancies. Accessed October 31, 2023. https://www.fda.gov/media/157762/download.
- U.S. Food and Drug Administration. Food And Drug Administration. Center For Drug Evaluation and Research. Oncologic Drugs Advisory Committee (ODAC) meeting. Virtual meeting. April 21, 2022. Accessed October 31, 2023. https://www.fda.gov/media/159920/download.
- U.S. Food and Drug Administration approves Gilead’s Zydelig® (idelalisib) for relapsed chronic lymphocytic leukemia, follicular lymphoma and small lymphocytic lymphoma. July 13, 2014. Accessed October 31, 2023. https://www.gilead.com/news-and-press/press-room/press-releases/2014/7/us-food-and-drug-administration-approves-gileads-zydelig-idelalisib-for-relapsed-chronic-lymphocytic-leukemia-follicular-lymphoma-and-small-lym.
- Restrictions on the use of Zydelig (idelalisib) for the treatment of chronic lymphocytic leukaemia (CLL) and relapsed follicular lymphoma (FL) following new clinical trial results. March 23, 2016. Accessed November 1, 2023. https://assets.publishing.service.gov.uk/media/5707baba40f0b60385000056/Zydelig__idelalisib__-_DHPC_sent_23_03_2016.pdf.
- U.S. FDA approves Imbruvica® (ibrutinib) as first treatment specifically indicated for relapsed/refractory marginal zone lymphoma (MZL) - a rare type of non-Hodgkin’s lymphoma. January 19, 2017. Accessed November 1, 2023. https://news.abbvie.com/2017-01-19-U-S-FDA-Approves-IMBRUVICA-ibrutinib-as-First-Treatment-Specifically-Indicated-for-Relapsed-Refractory-Marginal-Zone-Lymphoma-MZL-a-Rare-Type-of-Non-Hodgkins-Lymphoma.
- Skånland SS, Brown JR. PI3K inhibitors in chronic lymphocytic leukemia: where do we go from here?. 2023;108(1):9-21.
- U.S. Food and Drug Administration. FDA grants accelerated approval to umbralisib for marginal zone lymphoma and follicular lymphoma. February 5, 2021. Accessed November 1, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-umbralisib-marginal-zone-lymphoma-and-follicular-lymphoma.
- Gribben JG, Jurczak W, Jacobs RW, et al. Umbralisib plus ublituximab (U2) is superior to obinutuzumab plus chlorambucil (O+Chl) in patients with treatment naïve (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): results from the phase 3 Unity-CLL study. Blood. 2020;136(Suppl 1):37–39.
- TG Therapeutics. TG Therapeutics announces voluntary withdrawal of the BLA/sNDA for U2 to treat patients with CLL and SLL. April 15, 2022. Accessed November 1, 2023. https://ir.tgtherapeutics.com/news-releases/news-release-details/tg-therapeutics-announces-voluntary-withdrawal-blasnda-u2-treat.
- Kyowa Kirin. MEI Pharma and Kyowa Kirin provide regulatory update on zandelisib following meeting with the FDA. March 24, 2022. Accessed November 1, 2023. https://www.kyowakirin.com/media_center/news_releases/2022/e20220325_01.html.
- MEI Pharma and Kyowa Kirin announce discontinuation of zandelisib development outside of Japan following recent FDA meeting. December 5, 2022. Accessed November 1, 2023. https://www.businesswire.com/news/home/20221205005800/en/MEI-Pharma-and-Kyowa-Kirin-Announce-Discontinuation-of-Zandelisib-Development-Outside-of-Japan-Following-Recent-FDA-Meeting.
- Ghia P, Pluta A, Wach M, et al. Acalabrutinib versus investigator’s choice in relapsed/refractory chronic lymphocytic leukemia: lymphocytic leukemia: final ASCEND trial results. 2022;6(12):e801.