Ibrutinib and Rituximab for Untreated CLL: ‘Practice Changing’


The combination of ibrutinib (Imbruvica, Pharmacyclics/Janssen) and rituximab (Rituxan, Roche/Genentech) beat the current gold standard of fludarabine, cyclophosphamide, and rituximab (FCR) for young, fit patients with untreated chronic lymphocytic leukemia (CLL) in a large trial funded by the National Cancer Institute (NCI).

Ibrutinib plus rituximab showed superior progression-free survival (PFS) and overall survival (OS) compared with FCR, and was also less toxic.

Tait D. Shanafelt, MD

These results from the E1912 study were presented here at the American Society of Hematology (ASH) 2018 Annual Meeting.

“These findings have immediate practice-changing implications and establish ibrutinib as the single most effective first-line therapy for patients with CLL,” lead author Tait D. Shanafelt, MD, from Stanford University, California, told Medscape Medical News.

“These definitive results show why large trials like this that test new therapies in an effort to achieve clinically meaningful benefit for patients are so important,” said Richard F. Little, MD, of the Cancer Therapy Evaluation Program at NCI in a statement.

Shifting Landscape

How these new findings fit alongside other recent results with ibrutinib in CLL is now a matter for consideration.

As reported by Medscape Medical News, data from another large NCI-sponsored trial, the ALLIANCE study, also presented at ASH, showed that ibrutinib alone was superior to the combination of bendamustine-rituximab in elderly patients ≥ 65 years of age with CLL. The investigators concluded that ibrutinib alone is appropriate as initial treatment of CLL in this patient population.

Additionally, results from an industry-sponsored study, the phase 3 iLLUMINATE trial — also presented at ASH (abstract 691) and submitted for approval of an additional indication — showed that the combination of ibrutinib and obinutuzumab (Gazyva, Roche/Genentech) provided a 77% reduction in risk of progression or death compared with chlorambucil and obinutuzumab (HR: 0.23; 95% CI: 0.15 – 0.37; P < .0001).

Aaron T. Gerds, MD

So three trials presented at the meeting suggest, in turn, that ibrutinib alone, ibrutinib plus rituximab, or ibrutinib plus obinutuzumab, should be the new standard for CLL. How are clinicians to choose between these regimens when treating patients with CLL?

“This is an embarrassment of riches,” commented Aaron T. Gerds, MD, of the Cleveland Clinic Taussig Cancer Institute, Ohio, who moderated an ASH press briefing during which the new results were discussed.

Ultimately, clinicians will have to weigh all the factors before deciding on the choices before them, he observed.

He also said that E1912 and ALLIANCE, large cooperative group studies, are important and unbiased, adding they are trials that industry is not likely to conduct. The iLLUMINATE study is industry sponsored and supports a US Food and Drug Administration (FDA) label — another way to pursue a treatment option, he pointed out.

Shanafelt pointed out although the E1912 study is not industry sponsored, it is registered with and has endpoints approved by the FDA. The study met all its endpoints, he noted, and hopes this new partnership between the cooperative groups and the FDA will get a nod for non-industry sponsored treatment options.

With ibrutinib approved as a single agent to treat newly diagnosed CLL, the E1912 study is the first trial in younger patients in which an ibrutinib regimen (ibrutinib plus rituximab) was compared with the gold-standard FCR regimen, and shows that for most patients an ibrutinib regimen should be preferred, lead author Jennifer A. Woyach, MD, of the ALLIANCE study, told Medscape Medical News.

“With these data it is probably appropriate to treat patients with either ibrutinib or the combination of ibrutinib and rituximab,” said Woyach, who is at Ohio State University Comprehensive Cancer, Columbus.

After the ASH meeting, practicing clinicians are likely to offer ibrutinib monotherapy first-line to treatment-naive CLL patients, commented Kanti R. Rai, MD, from the Feinstein Institute of Medical Research at Hofstra/Northwell, Hempstead, New York.

“It is a game changer,” he said and added that physicians are experienced with and comfortable using ibrutinib.

Rai believes data from the ALLIANCE study are more likely to inform clinical practice and ibrutinib monotherapy will be the standard in treatment-naive CLL. “Physicians, patients, and society have become sensitive to the cost of therapy, and with single-agent ibrutinib one is likely to avoid unnecessary expense,” he said.

“The age group difference [younger versus older] between E1912 and ALLIANCE is not likely to be critical,” Rai observed.

“We do not know for sure whether the data from ibrutinib-rituximab versus ibrutinib in older patients [ALLIANCE population] is generalizable to the entire CLL population, and I do not believe this comparison will ever be repeated in younger patients, so I think it is probably reasonable to choose either ibrutinib alone or in combination with rituximab in younger patients,” Woyach told Medscape Medical News.

Shanafelt indicated that the ongoing FLAIR trial is likely to provide a more definitive answer. FLAIR, which is enrolling patients with treatment-naive CLL aged 18 to 75 years, is evaluating four treatment regimens: FCR, ibrutinib-rituximab, ibrutinib-venetoclax, and ibrutinib alone.

Both Rai and Woyach predict that FCR will be used less but is appropriate for certain patients, such as those with mutated IGVH disease (low risk). “Long-term data from the FCR studies shows that a proportion of low-risk patients have the potential for very long-term remission and even cure. We will have to see with long-term follow-up from the E1912 study whether ibrutinib-rituximab is superior to FCR in IGVH mutated patients because that is not clear at this time,” Woyach said.

Shanafelt told Medscape Medical News that both E1912 and ALLIANCE are cooperative group studies and were designed simultaneously prior to the approval of ibrutinib (in 2014). E1912 was conducted in patients ≤ 70 years of age and ALLIANCE in those ≥ 65 years of age. “There was an intentional overlap because some patients have robust health and can tolerate FCR,” he said. “Both trials met their endpoint at the same time and based on the age category, ibrutinib-based therapy is the most effective compared with the best historic regimens,” he said.

“For all comers independent of age, ibrutinib-based treatment is the standard of care based on data from the two studies,” Shanafelt told Medscape Medical News.

The E1912 Study Results

The E1912 trial was a randomized phase 3 study that enrolled 529 patients (2:1) to ibrutinib plus rituximab (n = 354) or standard FCR therapy (n = 175). Patients enrolled were ≤ 70 years of age and those with 17p deletion were excluded because of poor disease response to FCR.

Patients treated with the combination of ibrutinib and rituximab received ibrutinib daily on days 1-28 for each cycle until disease progression or unacceptable toxicity. Rituximab was given in cycles 1-7. Patients in the FCR group were given the drugs over 6 cycles, as is typical in clinical practice.

Median age of patients was 58 years and 41% were ≥ 60 years; 75% of patients had IGVH unmutated disease.

Results were presented for the first interim analysis performed September 2018. Median follow-up was 33.4 months.

For the primary endpoint of PFS, the combination of ibrutinib and rituximab was associated with a 65% reduced risk for progression or death (hazard ratio [HR], 0.35; 95% CI, 0.22 – 0.5; P < .00001). Three-year PFS was 89% for the ibrutinib-rituximab combination and 73% for FCR.

OS was also superior for the combination of ibrutinib and rituximab (HR, 0.17; 95% CI, 0.05 – 0.54; P < .0003).

The superiority of the combination of ibrutinib and rituximab was seen regardless of age, performance status, disease stage, or presence or absence of del11q23. The superiority was also established for IGVH unmutated but not IGVH mutated disease.

Grade 3/4 treatment-related adverse events were reported for 58% and 72% of patients receiving the ibrutinib regimen and FCR, respectively. Compared with ibrutinib plus rituximab, FCR was associated with a significantly higher incidence of grade 3/4 neutropenia (22.7% vs 43.7%), anemia (2.6% vs 12.0%), thrombocytopenia (2.9% vs 13.9%), and infectious complications (7.1% vs 19.0%).

Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma.


BACKGROUND

Bruton’s tyrosine kinase (BTK) is a mediator of the B-cell–receptor signaling pathway implicated in the pathogenesis of B-cell cancers. In a phase 1 study, ibrutinib, a BTK inhibitor, showed antitumor activity in several types of non-Hodgkin’s lymphoma, including mantle-cell lymphoma.

METHODS

In this phase 2 study, we investigated oral ibrutinib, at a daily dose of 560 mg, in 111 patients with relapsed or refractory mantle-cell lymphoma. Patients were enrolled into two groups: those who had previously received at least 2 cycles of bortezomib therapy and those who had received less than 2 complete cycles of bortezomib or had received no prior bortezomib therapy. The primary end point was the overall response rate. Secondary end points were duration of response, progression-free survival, overall survival, and safety.

RESULTS

The median age was 68 years, and 86% of patients had intermediate-risk or high-risk mantle-cell lymphoma according to clinical prognostic factors. Patients had received a median of three prior therapies. The most common treatment-related adverse events were mild or moderate diarrhea, fatigue, and nausea. Grade 3 or higher hematologic events were infrequent and included neutropenia (in 16% of patients), thrombocytopenia (in 11%), and anemia (in 10%). A response rate of 68% (75 patients) was observed, with a complete response rate of 21% and a partial response rate of 47%; prior treatment with bortezomib had no effect on the response rate. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95% confidence interval [CI], 15.8 to not reached), the estimated median progression-free survival was 13.9 months (95% CI, 7.0 to not reached), and the median overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.

CONCLUSIONS

Ibrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma.

Source: NEJM

 

Ibrutinib Highly Active in Patients with Chronic Lymphocytic Leukemia with 17p Deletion.


The targeted agent ibrutinib produced rapid and durable control of disease in both treatment-naïve and relapsed/refractory patients with 17p deletion chronic lymphocytic leukemia, according to the results of a study presented at the 12th International Conference on Malignant Lymphoma held June 19-22, 2013 in Lugano, Switzerland.

Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia. The American Cancer Society estimates that approximately 15,000 people will be diagnosed with CLL this year. Currently, there are approximately 95,000 people in the United States living with CLL.

CLL is characterized by the production of atypical lymphocytes. Lymphocytes are specialized immune cells that exist in two forms: B- and T-cells. These cells are produced in the bone marrow and each serves a specific function in aiding the body to fight infection. The large majority of CLL cases involve mature B-lymphocytes that tend to live much longer than normal. B-lymphocytes accumulate in the blood, bone marrow, lymph nodes, and spleen. This results in overcrowding of these areas and suppression of the formation and function of blood and immune cells. Additionally, the cancerous lymphocytes themselves do not function normally, leading to a further reduction in the body’s ability to fight infection.

Although there are effective treatments for CLL, some populations are harder to treat and tend to have worse outcomes. Many elderly patients are unable to tolerate current aggressive standard treatments. Also, individuals with a deletion in the short arm of chromosome 17 (referred to as del 17p) have poor outcomes with chemotherapy.

Ibrutinib is a selective inhibitor of Bruton’s tyrosine kinase, a component of the B-cell receptor signaling pathway that plays a key role in the development and progression of CLL. In other words, the targeted therapy attacks the pathway that mediates disease progression.

Researchers conducted a phase II, single-agent study that included 29 patients with del 17p CLL—15 who were treatment-naïve and 14 with relapsed/refractory disease. Patients were treated with 420?mg of ibrutinib daily until disease progression and response was evaluated at 6?months and every 6?months thereafter. After a median follow-up of 9 months, the results showed a promising response.

At 6 months, 88 percent of 25 evaluable patients had a nodal response (defined as 70% median reduction in lymph node size), 48 percent had a partial response by International Workshop on CLL (IWCLL) criteria, and 40 percent had a partial response with lymphocytosis. One patient had progressive disease (presumed transformation). Nodal response was observed in 93 percent of the patients with relapsed/refractory disease and in 82 percent of treatment-naive patients.

The estimated event-free survival at 12 months was 90 percent. All patients showed a reduction in splenomegaly, with a median reduction in spleen volume of 446 mL (46%) from baseline. At 6 months, the researchers repeated bone marrow biopsy and fluorescence in situ hybridization (FISH) measurement in 23 patients. The bone marrow biopsy revealted that tumor burden decreased by a median 76 percent (from baseline) as assessed by immunohistochemistry for CD79a. FISH was used to quantify the percentage of tumor cells with the 17p deletion—at 6 months, there was a median reduction of 55 percent in 15 out of 18 patients, no change in 1 patient, and an increase in 3 patients.

Treatment was tolerated—non-hematologic toxicities of grade 3 or higher were observed in 14 percent of patients. Two deaths occurred during the study, but were not considered treatment-related.

The researchers concluded that single-agent ibrutinib is effective in treatment-naïve and relapsed/refractory patients with del 17p CLL and produces rapid and durable control of disease. Research will be ongoing to evaluate single-agent inbrutinib as a strategy for this group of high-risk patients.

 

Reference:

Wiestner A, Farooqui M, Valdez J, et al. Single agent ibrutinib (PCI-32765) is highly effective in chronic lymphocytic leukemia patients with 17p deletion. Hematological Oncology: Special Issue: 12th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, June 19–22, 2013. 31 (SI): 96-150. Abstract 008.

 

Source: cancerconnect.com

 

Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia.


BACKGROUND

The treatment of relapsed chronic lymphocytic leukemia (CLL) has resulted in few durable remissions. Bruton’s tyrosine kinase (BTK), an essential component of B-cell–receptor signaling, mediates interactions with the tumor microenvironment and promotes the survival and proliferation of CLL cells.

METHODS

We conducted a phase 1b–2 multicenter study to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of ibrutinib (PCI-32765), a first-in-class, oral covalent inhibitor of BTK designed for treatment of B-cell cancers, in patients with relapsed or refractory CLL or small lymphocytic lymphoma. A total of 85 patients, the majority of whom were considered to have high-risk disease, received ibrutinib orally once daily; 51 received 420 mg, and 34 received 840 mg.

RESULTS

Toxic effects were predominantly grade 1 or 2 and included transient diarrhea, fatigue, and upper respiratory tract infection; thus, patients could receive extended treatment with minimal hematologic toxic effects. The overall response rate was the same in the group that received 420 mg and the group that received 840 mg (71%), and an additional 20% and 15% of patients in the respective groups had a partial response with lymphocytosis. The response was independent of clinical and genomic risk factors present before treatment, including advanced-stage disease, the number of previous therapies, and the 17p13.1 deletion. At 26 months, the estimated progression-free survival rate was 75% and the rate of overall survival was 83%.

CONCLUSIONS

Ibrutinib was associated with a high frequency of durable remissions in patients with relapsed or refractory CLL and small lymphocytic lymphoma, including patients with high-risk genetic lesions.

Source: NEJM