The results of a trial combining two novel agents in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) should serve as a cautionary tale to researchers developing novel agents.
The phase II dose-escalation study of idelalisib and entospletinib in 66 patients with relapsed/refractory CLL or NHL had to be terminated because of severe treatment-emergent pneumonitis in 12 patients (18%), including two who died. The study was published recently in Blood (2016;127:2411-2415).
The researchers pointed to the study design's rapid intrapatient dose escalation schedule and consequent short window for dose-limiting toxicity to explain the pneumonitis, which was life-threatening in 11 of the 12 patients. They recommend future clinical trials with novel agents be designed with an increased focus on safety, and thoroughly incorporate pharmacodynamics and other biomarker monitoring to predict unique toxicities.
“This clinical trial is a cautionary tale of why the classic manner in how we develop novel agents needs to remain as it has been, proceeding in a very conservative, cautious manner, where safety is our first priority,” said lead author Paul M. Barr, MD, Associate Professor of Medicine and Director of the Clinical Trials Office, James P. Wilmot Cancer Center, University of Rochester Medical Center in New York. “Future studies really need to keep this experience in mind.”
Barr said that, even without the trial's short dose-limiting toxicity window, the traditional monitoring period for dose-limiting toxicities would not have been sufficient given the relatively late occurrence of pneumonitis. “We suggest that similar future studies enroll patients without dose escalating individual patients.”
The study aim was to improve the depth of remission and durability of responses in CLL and NHL by combining idelalisib, a selective inhibitor of PI3-kinase (PI3K), with entospletinib, a small-molecule inhibitor specific to spleen tyrosine kinase that has been implicated in the pathobiology of B-cell lymphoid malignancies.
In vitro studies have shown that simultaneous inhibition of multiple kinases in the B-cell receptor signaling pathway can produce synergistic antitumor activity, suggesting the potential to improve the depth of clinical responses and to overcome treatment resistance.
In this study each patient underwent a relatively rapid dose escalation—idelalisib from 100 to 150 mg and entospletinib 200 to 800 mg twice daily—every 2-4 weeks.
The idelalisib/entospletinib combination was active. With median exposure to therapy of 10 weeks, overall response rates were 60 percent in the CLL cohort, 36 percent in the follicular lymphoma cohort, and 17 percent in patients with diffuse large B-cell lymphoma.
Exactly how related the various doses were to the pneumonitis is unclear, Barr said, because of the rapid intrapatient dose escalation and the delayed occurrence of pneumonitis.
Mean time to onset of pneumonitis was 12 weeks. Symptoms were characterized by acute-onset dyspnea, cough, hypoxia, and bilateral ground-glass infiltrates on CT scan, often accompanied by fever and chills.
The researchers reported most patients with pneumonitis recovered with supportive measures and systemic steroids. The non-infectious pneumonitis was accompanied by increases of cytokines/chemokines associated with immune-cell recruitment, including interferon-gamma and interleukins-6, -7, and -8. The increases started around week 4 and were most pronounced by week 12, long after the rapid dose escalations.
Researchers recommended future investigations prospectively evaluate plasma cytokine/chemokine levels in an attempt to validate biomarkers predictive of response and toxicity.
Other toxicities observed were treatment-emergent diarrhea, rash, and hepatic transaminase elevation, seen in 29 percent, 30 percent, and 23 percent of patients, respectively; but these were generally reversible with treatment discontinuation.
The FDA alerted health care professionals March 4 about reports of an increased rate of adverse events, including deaths, in clinical trials with idelalisib in combination with other cancer medicines. Six clinical trials in patients with CLL, small lymphocytic lymphoma, and indolent NHL have been stopped.
Idelalisib is currently FDA-approved by treatment of relapsed CLL in combination with rituximab in patients for whom rituximab alone would be considered appropriate; in relapsed follicular B-cell NHL in patients who have received at least two prior systemic therapies; and in relapsed small lymphocytic lymphoma in patients who have received at least two prior systemic therapies.
Idelalisib is not approved for previously untreated CLL.
Barr said his trial was not one of the six involved in this action. “Pneumonitis was known as a potential adverse event with idelalisib, as it is with most of the PI3K inhibitors, but it is rare, occurring in approximately 2-4 percent of patients,” he said. “But in this trial, it was 18 percent, a big surprise.”
Barr said that, interestingly, pneumonitis is now recognized as a complication across the PI3K inhibitors as well as in other classes of drugs, such as those that target the PD-1/PD-L1 axis.
“In fact, a lot of our novel agents that have pleiotropic effects on the immune system can cause such toxicities, another example of how we're learning as we develop these drugs,” he said.
Barr said two lessons can be learned from this trial:
“First, drug development is not for the faint of heart and we have to do it in a very safe and cautious manner, whether it's studying novel agents or using certain agents early on in the disease course. Dose escalation has to be slow and careful despite the pressure to move drugs through the pipeline. Second, it's important not only to monitor individual patients but also monitor the data sets very carefully.”
What Appears Safe Is Sometimes Not
An editorial accompanying this report in Blood summarized the balance researchers have to maintain in developing new treatments:
- Wants: maximizing dose for best response, and moving drugs quickly through the pipeline;
- Musts: more frequent and rigorous monitoring for toxicity, and increased use of biomarkers to predict toxicity (Blood 2016;127:2367-2368).
“A harmony between ‘musts’ and ‘wants’ in clinical trials is essential to ultimately increase survival,” said the authors, Spencer H. Bachow, MD, a fellow in oncology at Columbia University, and Nicole Lamanna, MD, Associate Professor of Medicine, Columbia University Medical Center.
This trial report “is an eye opener,” said Lamanna, the senior author, told Oncology Times. “It's a warning of what to be careful of with these exciting new agents.”
As anticancer treatment enters the new territory of novel targets, particularly with those agents that harness the power of the immune system, researchers are just now learning that these drugs can stimulate the immune system in a different manner from the traditional chemo-immunotherapy approaches used for decades, she said.
“And when we try to combine some of these, we realize we have to be more careful how we design clinical trials to allow more time to watch for possible unanticipated side effects that may develop, particularly some of these inflammatory mediated responses such as pneumonitis.”
Lamanna noted pneumonitis has been seen with this class of drugs, “but clearly the combination for some reason enhanced the side effect. We don't know the true mechanism.”
Dose escalations were allowed every 2-4 weeks, which might not have been enough time between escalations to observe side effects and begin to intervene soon enough, she explained.
Lamanna said there is another side to this balancing act—protecting patients, but not in a way that prevents a potentially active drug from being studied. “We've lost some good drugs that might have shown activity against a certain cancer, but they were nixed because they had side effects that we had to learn to deal with,” she concluded.
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