Ibrutinib and rituximab provides superior PFS and OS compared to FCR for younger patients with previously untreated CLL

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Published: 6 Dec 2018
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Dr Tait Shanafelt - Standford University, Stanford, USA

Dr Tait Shanafelt gives a press conference at ASH 2018 on the findings of the E1912 which show the combination of ibrutinib and rituximab to be superior to FCR chemoimmunotherapy for younger patients with previously untreated CLL.

Watch his interview with ecancer here.

Read more about this work here.

The ECOG-1912 trial evaluated whether we could improve upon the best current treatment for patients with CLL. This is one of our most common lymphoid malignancies and to date this combination of chemotherapy using fludarabine, cyclophosphamide and rituximab has been our most active therapy. But it’s a therapy with high side effects and cannot be tolerated by all CLL patients, primarily only administered to those aged 70 and younger. Since the median age of this disease is right around 70 half of the patients are not even able to tolerate the most effective therapy but for the younger patients this is the preferred treatment.

Ibrutinib is a targeted therapy. Over the last five years we’ve had better understanding of this specific signalling pathway in CLL, called the B-cell receptor pathway, which is really the Achilles heel of CLL, necessary for these cells to survive. This pill-based therapy targets the Bruton’s tyrosine kinase in that pathway. Although the agent has been shown to be effective as an initial treatment for older patients, we have never had good trials comparing it to our most effective chemoimmunotherapy regimens such as FCR.

The E1912 trial, the schema is shown for you here. This is a National Cancer Institute sponsored trial. It was accrued to across the North American intergroup, so led by ECOG but all US groups participated, for CLL patients aged 70 and younger who had not been previously treated. Two out of every three patients received the experimental therapy, the ibrutinib and rituximab combination. They received the pill-based therapy for one month; the second agent, the rituximab, is added in month two, they received that along with the pill once a month for six months and then continue on the pill-based therapy as long as they’re tolerating it and as long as it’s controlling their leukaemia. The other arm, the standard arm, received six cycles or six months of therapy with this three drug chemotherapy combination.

The patient characteristics are shown here. A couple of things to note: the median age here in the late 50s and, again, if we look at the whole population of CLL patients this is a younger group, the group with perhaps the biggest impact of their CLL on life expectancy because they’ve developed this leukaemia at a younger age. When we look at these different stage characteristics and genetic characteristics, these other parameters here, this largely shows that this also was a higher risk group than some of our historical trials that developed the FCR regimen.

This curve shows the progression free survival of the targeted therapy, ibrutinib and rituximab in red, the standard chemotherapy in the dashed black line, and you note that the novel therapy is improving the disease control with longer progression free survival. The overall survival curve is also shown here and you’ll note that this is a statistically significant difference with a markedly lower risk of death in the patients receiving the new therapy relative to the standard chemotherapy.

With respect to side effects, I would emphasise that the new therapy was also less toxic than our historical therapy. So obviously in cancer trials, as physicians, we want to improve the effectiveness of treatment or reduce its side effects. This trial is one of the rare circumstances where we’ve done both with a single therapy.

The conclusions are that ibrutinib and rituximab based therapy improves both progression free survival and overall survival compared to our historical best treatment which was a chemotherapy based platform. The regimen is well tolerated and actually had fewer side effects than our standard previous therapy. This establishes ibrutinib-based therapy as the most effective treatment tested to date in this disease for untreated patients. Happy to discuss in the question session. There’s also a paradigm shift from a six month course of intravenous chemotherapy to chronic treatment with a pill that this trial brings about. So one of the new questions on the horizon is can we use combinations of some of these targeted new therapies to see if we can eliminate that need for chronic therapy? There are two new trials, also both sponsored by the National Cancer Institute, which will activate this month to try and explore that question.