On January 19, 2017, the United States Food and Drug Administration (FDA) approved ibrutinib to treat patients that have received at least one line of prior therapy for marginal zone lymphoma (MZL), a type of non-Hodgkin lymphoma (NHL).
MZL is an indolent B-cell lymphoma that accounts for 5-10% of all lymphomas and lacks a standard of care. Current MZL treatments include anti-CD-20 antibody therapy (e.g. rituximab) or chemotherapy. However, ibrutinib is the first-ever treatment to specifically be approved for MZL.
Ibrutinib works by inhibiting Bruton’s tyrosine kinase (BTK), an enzyme responsible for transmitting pro-growth and survival signals from the surface of a cell to its nucleus. In this way, ibrutinib may interfere with chronic stimulation arising from inflammation in the tumor microenvironment; thus slowing the growth of B-cells.
The Weill Cornell Lymphoma Program is proud to have played a role in the phase 2 trial — the largest trial to date for people with previously treated MZL of all subtypes —leading to FDA approval for ibrutinib. Roughly half of all patients had a significant response to ibrutinib, with some degree of tumor shrinkage observed in almost 80% of all patients in the trial. Roughly one-third remained on treatment 18 months after beginning treatment.
The most common side effects included fatigue, diarrhea, and anemia. These side effects were manageable, and consistent with previous research, although some cases required the discontinuation of treatment with ibrutinib.
Results from this study support the use of ibrutinib as an effective well tolerated chemotherapy-free option for the treatment of previously treated MZL. However, some questions remain. MZL is a heterogeneous group of lymphomas, and it is unclear which subtypes might respond best to ibrutinib. With only half of all previously treated MZL patients responding to ibrutinib, improvements might be realized by combining ibrutinib with other drugs and/or using it earlier in the treatment of MZL.
At Weill Cornell, we are currently studying ibrutinib in combination with the immunotherapy drug durvalumab in people with previously treated indolent non-Hodgkin lymphoma, including MZL.
Splitting her time between the main Cornell campus in Ithaca and the Weill Cornell Medical campus in New York City, Dr. Kristy Richards has developed a unique plan to research new lymphoma treatments. Lymphoma is a common form of cancer in humans and also the most common form of cancer found in dogs. So as human oncologist, Dr. Richards thought that treatments for canine patients could lead to advances in the treatment of human lymphoma patients,
“Dog and human lymphoma patients share many biological similarities, as well as the unfortunate fact that rates of the disease are rising for both species. “We don’t know why this is,” Richards says. “It could be something in the environment, which both dogs and humans share. So in a way, dogs could be a canary in the coal mine.”
“Richards plans to test cutting-edge approaches such as immunotherapy, which harnesses the body’s natural defenses to fight off cancer cells, in dogs suffering from lymphoma. This September, she was awarded a supplement grant from the National Cancer Institute, in partnership with the Roswell Park Cancer Institute in Buffalo, to further explore canine immunotherapy with veterinary patients that come to the Cornell University Hospital for Animals.”
The full article can be read here. More information about Dr. Richards work and the practical benefits so far accrued for both two and four legged lymphoma patients can be found in the below video.
Recently researchers from the Mayo Clinic presented data at the 2016 ASCO annual meeting suggesting that clinical trial participation might be associated with a survival benefit. The researchers used the Mayo Clinic Lymphoma Database to identify patients with relapsed Hodgkin lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), or relapsed mantle cell lymphoma (MCL), and compared the characteristics and outcomes of those enrolled in clinical trials versus those who were eligible, but not enrolled in clinical trials. Between January 2001 and December 2014, 340 patients with DLBCL, 159 with MCL, and 115 patients with HL were identified. Over this same period 47 unique Phase 1-3 trials led to the FDA approval of 17 treatments.
94 of 340 (27%) DLBCL, 63 of 159 (41%) MCL and 66 of 115 (57%) HL patients were enrolled on a clinical trial at some point during therapy, with 38% of patients enrolled in more than 1 study. Researchers found that the median survival of patients treated in a clinical trial was roughly twice as long as patients not treated on a clinical trial in all 3 lymphoma subtypes. There are several possible sources of bias or confounding that might explain the difference, despite the researchers’ efforts to control for these variables. Clearly, more research in this areas is indicated. Nonetheless, the magnitude of benefit was striking and should be reassuring to patients considering clinical trial participation.
In addition to providing the best possible care for people with lymphoma, one of our primary goals in the Weill Cornell Lymphoma Program is to help develop better treatments. To keep track of these approvals we have created the Lymphoma Therapy Approval Timeline page on our blog. The timelines lists all of the new Breakthrough Designations, and approvals generated by the FDA for therapies related to the treatment of lymphoma. More in-depth information about these approvals can be found our blog.
So far, 2016 has been an eventful year, with six drugs receiving an updated approval status or Breakthrough Therapy Designation for the treatment of lymphoma. At the same time, recent circumstances have led to the closure of at least seven clinical trials evaluating the role of idelalisib. In the face of all this activity, it is clear that we are keeping the FDA busy. People in my clinic ask me almost every day, “Why does it take the FDA so long to approve promising new drugs?” To help answer this question I will write a series of blog posts summarizing the drug development process. An in-depth explanation of the process can be found on the FDA website.
Today, in the first post of the series, I thought it would be interesting to address whether the FDA is a bureaucratic wall standing between patients and potentially lifesaving cancer therapy, whether the FDA has become too lax in its approval process, resulting in approval of dangerous drugs or labels that are too broad, or whether it gets the balance just right.
In 2014 Yale University researchers published a study that sought to characterize how new treatments were approved by the FDA between 2005 and 2012. Of the 188 new treatments included in the study the largest group were cancer treatments at 41 (19.9%). Compared to other indications, cancer treatments were more frequently approved through less time consuming non-randomized, non-blinded studies, and accelerated approval programs. Instead of using standard clinical outcomes, nearly all of these trials measured surrogate end points like reduced tumor size or decreased biomarker levels. These endpoints can be reached in shorter periods of time than clinical outcomes like overall survival. The study authors noted that while treatments for other indications generally relied on 3 trials, “Most therapeutic agents approved for cancer indications were approved on the basis of a single trial.”
Some of these recent approvals likely reflect that fact that we are in the midst of a scientific revolution, with an explosion of new drugs that are clearly superior to older therapies becoming available at an unprecedented rate. But it is also clear that the FDA is aware that people with cancer face unique circumstances and are willing to move forward with new drugs at a faster rate. If you have any specific questions or experiences that you’d like us to cover in this series of posts, let me know and I’ll do my best to address them. Stay tuned!
In this video from OncLive, Lymphoma Program Director, Dr. John Leonard addresses the question of when is the best time to treat patients with follicular lymphoma. Noting that the majority of follicular lymphoma patients will not die from their disease, he suggests treatment should be based on symptomatic progression.
On March 14, three days after a similar announcement from the European Medicines Agency (EMA) the Food and Drug Administration (FDA) issued an alert to healthcare professionals concerning the use of idelalisib (Zydelig) in combination with other cancer treatments. Following reports of increased adverse events including deaths linked to idelalisib during clinical trials, Gilead Sciences, stopped six clinical trials for patients with chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), and indolent non-Hodgkin lymphoma.
Idelalisib is currently approved for use in relapsed CLL, in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities, relapsed follicular B-cell non-Hodgkin lymphoma in patients who have received at least two prior systemic therapies, and relapsed SLL in patients who have received at least two prior systemic therapies. These approvals were based on phase 2 and phase 3 studies that had demonstrated significant evidence of benefit relative to standard therapies. The recent FDA/EMA announcements have not commented on the approved indications for idelalisib.
Doctors at Weill Cornell Medicine take patient safety very seriously. Patients currently taking idelalisib are encouraged to discuss any concerns they may have with their physician.