Ibrutinib Bests Temsirolimus in Relapsed/Refractory Mantle Cell Lymphoma


Ibrutinib sparks more durable remissions than temsirolimus in patients with relapsed or refractory mantle cell lymphoma.

Simon Rule, MD

Treatment with ibrutinib (Imbruvica) sparked more durable remissions than temsirolimus in patients with relapsed or refractory mantle cell lymphoma (MCL), a phase III study has found.1

Data demonstrating a 57% reduction in the risk of progression with ibrutinib compared with temsirolimus were among the findings of the randomized international RAY study, presented during the 2015 ASH Annual Meeting and simultaneously published in the journal The Lancet.2

Determining which drugs can bring the most benefit in the relapsed/refractory setting is crucial to patients with MCL, said lead investigator Simon Rule, MD, a consultant in the Department of Haematology and head of the Lymphoma Service at Derriford Hospital in Plymouth, United Kingdom, in presenting the data during an oral session.

He said these patients face a poor overall prognosis due to the aggressive nature of this B-cell lymphoma. They typically progress after first-line therapy, experience only short-term remissions using conventional chemotherapy, and have a median overall survival of 1 to 2 years, Rule said.

He said the two drugs in the study were compared head-to-head because ibrutinib, a Bruton tyrosine kinase, has been shown in previous studies “to be highly active for previously treated MCL patients,” with an overall response rate (ORR) of about 65%. In 2013, the FDA granted accelerated approval to ibrutinib for the treatment of patients with MCL who have received at least 1 prior therapy.

Patients taking the mTOR inhibitor temsirolimus have demonstrated longer progression-free survival (PFS) than those on investigator’s choice of treatment, according to the abstract presented at the meeting. Temsirolimus is an approved standard of care for patients with relapsed/refractory MCL in the European Union, but is not indicated in MCL in the United States.

The 280 patients in the study, whose median age was 68, had experienced disease progression after a median of 2 prior therapies, including at least 1 rituximab-containing therapy. Most participants had stage IV intermediate- or high-risk disease.

Enrolled between December 2012 and November 2013, the patients were randomized 1:1 to receive 560 mg of oral ibrutinib daily (n = 139) or 175 mg of intravenous temsirolimus (n = 141) on days 1, 8, and 15 of cycle 1, with the dose dropping to 75 mg in subsequent cycles. In both arms, treatment continued until disease progression or unacceptable toxicity.

The primary endpoint was PFS as assessed by an independent review committee (IRC), and secondary endpoints included overall survival (OS), ORR, time to worsening of disease symptoms (TTNT), time to next treatment (TTNT), and safety.

At a 20-month follow-up, ibrutinib met its PFS endpoint with a 57% reduction in the risk of progression or death compared with temsirolimus; median PFS was 14.6 months with ibrutinib and 6.2 months with temsirolimus (HR, 0.43; 95% CI, 0.32-0.58; P < 0.0001). At 2 years, the PFS rate was 41% with ibrutinib and 7% with temsirolimus. PFS results were consistent across most assessed subgroups, and investigator-assessed PFS was consistent with the IRC results, the authors reported.

By IRC assessment, the ORR was 71.9% in the ibrutinib arm versus a 40.4% ORR in the temsirolimus arm (P < 0.0001), with a complete response (CR) rate of 18.7% (26 patients) versus 1.4% (2 patients), respectively.

At the time data were locked, median OS had not been reached in the ibrutinib arm, and was 21.3 months with temsirolimus. This indicated a positive trend favoring the ibrutinib arm, reported authors, who stated that there was a 24% reduced risk of death with ibrutinib (HR, 0.76). This difference might have been greater, the investigators wrote, if the results had not been confounded by the crossing over to the ibrutinib arm of 23% of those initially enrolled in the temsirolimus arm (32 patients).

At a 20-month follow-up, 42% of patients in the ibrutinib group had died compared with 45% of patients in the temsirolimus group, according to a press release issued by ibrutinib’s developer, Janssen Biotech, Inc. With ibrutinib, the most common cause of death was disease progression; with temsirolimus, the primary cause was adverse events, the release stated.

Quality of life appeared better with ibrutinib, as 27% of patients taking ibrutinib experienced a worsening of symptoms versus 52% of patients taking temsirolimus. Median TTNT was 11.6 months for those taking temsirolimus, but had not been reached in the ibrutinib arm.

Rule also reported on patients’ overall response to later lines of anticancer therapy given after progression on either ibrutinib or temsirolimus. Adjusted for crossover, it was about 20% in each group, with more complete responses occurring in those who received therapy after ibrutinib than after temsirolimus. The investigator added that median PFS was 19.1 months in patients treated following ibrutinib and 11.3 months in patients treated after temsirolimus.

Finally, Rule discussed how patients had fared on the 2 study drugs in relation to the number of prior therapies they had received. He noted that patients were more likely to respond to ibrutinib than to temsirolimus after 1, 2, or 3 prior therapies.

For example, after 1 prior therapy, 71.9% of patients responded to ibrutinib, including 24.6% who had complete responses, versus 48% of patients responding to temsirolimus, including 2% who had complete responses. After 3 prior therapies, 75% of patients responded to ibrutinib, including 11.4% who had complete responses, and 33.3% responded to temsirolimus, with none having complete responses.

Patients stayed on temsirolimus for a median 3 months and on ibrutinib for a median 14.4 months. Overall, 12.9% of patients discontinued treatment due to adverse events (AEs) in the ibrutinib arm and 29.5% did so in the temsirolimus arm, Rule reported during his presentation.

For those taking ibrutinib, the most common AEs were diarrhea, fatigue, and cough, the authors reported. For those taking temsirolimus, the most frequently observed AEs were thrombocytopenia, anemia, and diarrhea. Grade 3 AEs were reported for 67.6% of ibrutinib patients versus 87.1% of temsirolimus patients; most frequent were thrombocytopenia, anemia, and neutropenia.

AEs of grade 3 or higher included atrial fibrillation, which affected 4% of those taking ibrutinib (5 patients) and 1% of those taking temsirolimus (2 patients), although those patients were predisposed to the condition and none discontinued treatment as a result. Another grade 3 or higher AE was major bleeding, reported in 10% of those taking ibrutinib (14 patients) and 6% of those taking temsirolimus (9 patients), according to the Janssen press release.

Secondary malignancies, mostly non-melanoma skin cancers, occurred in 3.6% of the ibrutinib population and 2.9% of the temsirolimus population. When adjusted to reflect a patient’s level of exposure to the drug taken, AE incidence was lower in the ibrutinib arm than in the temsirolimus arm, the authors wrote in the abstract.

“Ibrutinib is superior to temsirolimus for PFS and ORR, and showed preferable tolerability,” the authors concluded. “The results of this phase III trial confirm the efficacy and favorable safety profile of ibrutinib shown in phase II studies. This study provides further evidence that ibrutinib should be considered the treatment of choice for patients with previously treated MCL.”

A next step should be to study ibrutinib in combination with other treatments for patients with relapsed or refractory MCL, the authors suggested. Ibrutinib should also be investigated for use earlier in the course of MCL, Rule said.


  1. Rule S, Jurczak W, Jerkeman M, et al. Ibrutinib versus temsirolimus: results from a phase 3, international, randomized, open-label, multicenter study in patients with previously treated mantle cell lymphoma. Presented at: the 57th Annual Meeting of the American Society of Hematology; Dec 5-8, 2015; Orlando, Florida. Abstract 469.
  2. Dreyling M, Jurczak W, Jerkeman M, et al. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study [published online December 7, 2015]. Lancet. doi: http://dx.doi.org/10.1016/S0140-6736(15)00667-4.


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