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%).