Phosphoinositide 3-kinase (PI3K) inhibitors represent a highly active class of drug for the treatment of chronic lymphocytic leukemia (CLL). Idelalisib (Zydelig), a PI3K-delta inhibitor and the first PI3K inhibitor to be approved by the U.S. Food and Drug Administration (FDA) for CLL, has impressive activity but has been complicated by toxicity. Nevertheless, the drug may still have value in treatment of the disease, according to a presentation at the 2017 International Workshop on CLL (iwCLL).1
“There are still some potential roles for idelalisib in the treatment of CLL,” explained Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute, Boston. “Possible settings for idelalisib include its use as a single agent or with rituximab (Rituxan) in patients intolerant to or relapsed after Bruton’s tyrosine kinase inhibitors, while use could expand if research identifies a good biomarker for tolerance, an alternative schedule, or a combination that might mitigate toxicity,” she suggested.
When using idelalisib, oncologists should be vigilant about potential toxicity, she cautioned. With current evidence, she added, idelalisib should be reserved for the relapsed setting.
There are still some potential roles for idelalisib in the treatment of CLL.— Jennifer R. Brown, MD, PhD
Two new PI3K inhibitors are under study—duvelisib and TGR-1202—and may represent better alternatives than idelalisib, but further studies are needed to establish their efficacy and tolerability. The hope is that one or both of these agents will be at least as efficacious as idelalisib with improved tolerability, but it is still early days for both drugs.
“Idelalisib [and probably duvelisib] cause a characteristic pattern of immune-mediated toxicity that is currently unpredictable and may be severe, particularly in less heavily pretreated patients,” Dr. Brown said. “Studies show that this toxicity is associated with less prior therapy, younger age, mutated IGHV, and decreased regulatory T cells on idelalisib. If controlled, this immune activation could represent an opportunity to use PI3K-delta inhibitors as antitumor immune-modulatory agents, even for example in solid tumors.”
Several clinical trials have shown that idelalisib is highly active in relapsed/refractory and untreated CLL. In the pivotal study that led to approval of idelalisib plus rituximab in previously treated, relapsed CLL (study 116), median progression-free survival was 19.4 months with the combination of idelalisib plus rituximab vs 7.3 months for rituximab plus placebo (P < .0001).2 In all patients, median overall survival was not reached in the combination therapy arm vs 20.8 months in the rituximab plus placebo arm (P = .0001). Results were similar for progression-free survival regardless of IGVH and TP53 mutation status.3
“Idelalisib plus rituximab shows very high overall response and excellent progression-free survival, even in patients with high levels of comorbidity. So what is the problem? Why is all the attention focused on ibrutinib?” she asked listeners.
The answer is the toxicity profile. In four studies of idelalisib with a total of 369 patients, 288 discontinued treatment; 150 (44%) withdrew due to adverse events, and 57 (15.4%) due to disease progression. Analysis of toxicity revealed a characteristic pattern, with grade 3 and 4 toxicities more common in less heavily pretreated patients and younger patients.
“The fact that serious adverse events are more common in less heavily pretreated patients and in younger patients is an unusual observation that suggests a novel mechanism that might be immune-mediated,” Dr. Brown suggested.
These toxicities include diarrhea/colitis, elevated transaminase, pneumonitis, and rash. Dr. Brown noted that idelalisib can be withheld for grade 3 or higher transaminase elevations and for grade 3 or higher rash, and the majority of patients can be successfully rechallenged.
“Pneumonitis is generally rare, but when it occurs, it is serious. Rechallenge is more difficult for this adverse event,” she said.
The major toxicity of concern with idelalisib is diarrhea/colitis. Grade 3 or higher diarrhea/colitis was reported in 14% of patients in study 116. This is a late event, occurring a median of 7 months after treatment initiation.
“I had one patient who developed colitis several years later, and it can recur when the drug is restarted. Be vigilant about these toxicities,” she cautioned.
A phase II trial of idelalisib plus ofatumumab (Arzerra) led by Dr. Brown in previously untreated CLL sheds some light on toxicity.4 A total of 24 subjects were enrolled in the trial, with a median time on therapy of 8 months. At a median follow-up of 14.7 months, 52% had grade 3 or 4 hepatotoxicity. Younger age and mutated IGVH predicted the occurrence of severe hepatotoxicity.
“I suspect that is why we don’t see this severe hepatotoxicity in the company-sponsored upfront clinical trials that enrolled only patients older than age 65,” she said. “Taken together, the evidence suggests that early hepatotoxicity is likely due to on-target immune-mediated effects,” Dr. Brown stated.
To explore this, the investigators studied 15 CLL patients prior to therapy and 1 month after therapy who developed hepatotoxicity. Patients who developed hepatotoxicity had a marked decrease in regulatory T cells, whereas those who did not develop toxicity had stable regulatory T cells. “This is a possible explanation for the fulminant hepatotoxicity seen in younger patients on front-line idelalisib,” Dr. Brown commented.
As a result of toxicity reports, Gilead halted several upfront studies of idelalisib. An increase in the rate of death was observed in previously untreated patients, but not in pretreated patients. Most of these deaths were primarily due to routine bacterial infections, neutropenia, and sepsis, not opportunistic infections and not autoimmune toxicity.
“Prophylaxis is important if you are using idelalisib,” she emphasized. “Idelalisib is highly active in relapsed/refractory and untreated CLL, but the drug is associated with several categories of toxicity, including autoimmune toxicity, neutropenia, and opportunistic infection.”
“With the current information we have, the use of idelalisib in CLL is most appropriate after CLL relapse,” she stated.
Duvelisib and TGR-1202
“PI3K inhibitors are highly active and are still much needed in B-cell malignancies. I and others have patients whose disease progresses on ibrutinib (Imbruvica) and venetoclax (Venclexta),” she told the audience. Two other PI3K inhibitors show promise in CLL: duvelisib, an oral inhibitor of PI3K-delta and PI3K-gamma, and TGR-1202, a next-generation PI3K-delta inhibitor with other targets.
Phase I data identified the 25-mg twice per day dose of duvelisib to take forward in CLL. The nodal response rate was 83% in patients with relapsed/refractory CLL. At 2 years, median progression-free survival has not been reached; 59% of patients have remained progression-free.
Dr. Brown described limited data on six patients previously treated with ibrutinib who relapsed and received duvelisib. The overall median time on treatment with duvelisib is 4 months. “We don’t know much about the use of PI3K inhibitors like duvelisib in the ibrutinib-progressing population. We need more data,” she said.
TGR-1202 has a different safety profile compared with the other two PI3K inhibitors. The data are preliminary, and of the 81 patients treated, 52 were treated at higher doses. About one-quarter have been treated for longer than 12 months. In a small number of patients, the overall response rate is 88%.
In early follow-up of TGR-1202 recipients, grade 3 and 4 adverse events have been limited. Only 2% of patients have had grade 3 or 4 elevations in liver enzymes, and 5% had grade 3 pneumonia. To date, no colitis has been reported. Six patients (7%) had to stop treatment due to adverse events.
“Why are the toxicities of TGR-1202 different? It is likely that the toxicities of idelalisib and duvelisib are on-target effects. We don’t know for sure about TGR-1202. It may have additional targets other than PI3K-delta,” she noted. ■
DISCLOSURE: Dr. Brown has served as a consultant for Gilead, Infinity, and TG Therapeutics and has received research funding from Gilead.
1. Brown J: Where are we with PI3K isoform inhibitors in CLL? 2017 International Workshop on Chronic Lymphocytic Leukemia. Presented May 15, 2017.
2. Furman R, Sharman J, Coutre S, et al: (2014b) Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 370:997-1007, 2014.
3. Sharman JP, Couture SE, Furman RR, et al: Second interim analysis of a phase 3 study of idealisib (Zydelig) plus rituximab for relapse chronic lymphocytic leukemia: Efficacy analysis in patient subpoplations with del(17;) and other adverse prognostic factors. 2014 ASH Annual Meeting. Abstract 330.