Lead iLLUMINATE study author Carol Moreno, MD, PhD, discusses the safety and efficacy results from the iLLUMINATE trial which led to the FDA approval of ibrutinib plus obinutuzumab in CLL.
Carol Moreno, MD, PhD
In findings from the phase III iLLUMINATE trial, the combination of ibrutinib (Imbruvica) plus obinutuzumab (Gazyva) proved to be a promising treatment option for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
Data presented during the 2018 ASH Annual Meeting showed the combination led to a 77% reduction in the risk of disease progression or death for patients with CLL/SLL and an 85% reduction for patients with high-risk CLL. After 31.3 months of follow up, the median PFS had not yet been reached in the ibrutinib plus obinutuzumab compared to 19 months in the chlorambucil and obinutuzumab arm of the trial.
Based on these findings,the combination gained FDA approval in January 2019for the treatment of patients with CLL or SLL.
In an interview withTargeted Oncologyduring the ASH Annual Meeting,lead iLLUMINATE study author Carol Moreno, MD, PhD, consultant hematologist, Hospital de la Santa Creu Sant Pau, Autonomous University of Barcelona, Barcelona, Spain, discussed the safety and efficacy results from the iLLUMINATE trial.
TARGETED ONCOLOGY:What was the rationale for this trial?
Moreno:Ibrutinib, as you already know, is a BTK inhibitor that has been approved for patients with CLL. As a single agent, ibrutinib has shown impressive results in terms of efficacy and safety after 7 years of follow-up. Recommended first treatment in patients older or those with comorbidities are either single-agent ibrutinib or conventional chemoimmunotherapy with chlorambucil plus obinutuzumab. We already know that patients with high-risk features or those with unmutatedIGVHdisease have suboptimal outcomes under chemoimmunotherapy.
Therefore, in the iLLUMINATE study, we investigated whether an addition of obinutuzumab to ibrutinib will improve PFS compared to conventional chemoimmunotherapy chlorambucil/obinutuzumab as first-line therapy. We also aim, prospectively, to confirm the superiority of ibrutinib plus obinutuzumab over conventional chemoimmunotherapy in patients with high-risk genomic features.
TARGETED ONCOLOGY:How was this trial designed?
Moreno:This was a randomized trial in which patients were eligible if they had previously untreated CLL and require therapy according to the NCCN CLL guidelines. Patients were randomized to receive either ibrutinib given continuously in combination with obinutuzumab for 6 cycles, which are given intravenously, or chlorambucil for 6 cycles in combination with obinutuzumab for 6 cycles.
TARGETED ONCOLOGY:What were the results reported at the meeting?
Moreno:The results are impressive because what we are seeing is that the combination of ibrutinib plus obinutuzumab resulted in superior PFS compared to conventional chemoimmunotherapy. The median PFS has not been reached after 31 months of follow-up in the ibrutinib plus obinutuzumab arm, while the median PFS was only 19 months in those patients receiving the conventional chemoimmunotherapy.
In addition, what is very relevant is that in this study, there was a high proportion of patients with high-risk genomic features. Sixty-five percent of the patients were unmutated or had high-risk features such as deletion of 11q, deletion of 17p, orTP53mutations. In this particular population of very high-risk patients, we are seeing the magnitude of the effect on PFS was also observed.We saw significant improvement in terms of PFS in this high-risk population treated with ibrutinib plus obinutuzumab while the outcome of these patients receiving conventional chemoimmunotherapy was very poor with a median of only 14 months.
TARGETED ONCOLOGY:What was the safety profile for the ibrutinib/obinutuzumab combination?
Moreno:The overall safety profile is consistent with the adverse events associated with each of the individual agents. We already know that ibrutinib single-agent has already been approved and obinutuzumab has also been approved in combination with chlorambucil. The profile is quite good, and we have not seen a higher rate of grade 3 or higher adverse events more frequently in the ibrutinib plus obinutuzumab arm compared to chlorambucil plus obinutuzumab.
In other words, the frequency of grade 3 adverse events or higher are the same in both treatments, even considering the fact that the exposure to the treatment is 6 times longer in the ibrutinib plus obinutuzumab arm compared to the conventional chemoimmunotherapy, which is given only for 6 cycles.
TARGETED ONCOLOGY:What is the main takeaway from these data?
Moreno:The takeaway from this trial is that in addition to single-agent ibrutinib, the combination of ibrutinib plus obinutuzumab offers another option to achieve a long-term PFS in patients with CLL.
TARGETED ONCOLOGY:What do we know about which patients are more likely to respond?
Moreno:All patients responded very well. We don’t know of any predictive factor, but what we have seen is that all patients independent of high-risk genomic features respond well to the combination of ibrutinib plus obinutuzumab. The responses are independent of the high-risk features.
TARGETED ONCOLOGY:Are there any questions that still exist in terms of these findings?
Moreno:In this trial, unfortunately, we couldn’t compare ibrutinib plus obinutuzumab to ibrutinib as a single agent. This is still the question, whether anti-CD20 monoclonal antibodies will offer a measured benefit for the patients compared to single-agent ibrutinib.
We will have this therapeutic option to treat these patients with CLL, but we still need to figure out which kind of population will benefit more from the combination instead of single-agent ibrutinib. With the combination of ibrutinib plus obinutuzumab, we are able to see higher complete response rates and higher undetectable minimal residual disease (MRD) rates, which is of great importance. When we discontinue therapy, for example, because of adverse events, it’s probably better to get rid of the disease early after therapy, then continue therapy indefinite for a long period of time, seeing that there is still disease over time.
TARGETED ONCOLOGY:If a trial confirms ibrutinib monotherapy is superior, do you still see a place for this combination in the field?
Moreno:That’s a very good question. Indeed. In this meeting, the ALLIANCE trial compared ibrutinib single-agent to ibrutinib with rituximab (Rituxan), which is another anti-CD20 monoclonal antibody. Although it is less potent than obinutuzumab, which was included in our study, versus conventional chemoimmunotherapy. The trial showed that rituximab didn’t add any benefit to single-agent ibrutinib. In our trial, with the combination of obinutuzumab, we are able to achieve deeper responses, but we still don’t know whether this will translate to prolonging the PFS.
We will know, in longer follow-up, [whether] the duration of remissions will be longer than single-agent ibrutinib. My guess is that with the use of an anti-CD20 monoclonal antibody, we may not prolong PFS, but we are able to get rid of the disease at least sooner because we have a complete response rate that is near 40% and undetectable MRD in 35% of the patients, which is for sure going to be good, particularly for those patients who are very high-risk in which we will be able to see if we have any sign of the disease.
TARGETED ONCOLOGY:Is there anything else you would like to highlight about this combination?
Moreno:Another important issue is that in a chronic disease like CLL, ibrutinib plus obinutuzumab reduces the need for a second therapy. With the conventional chemoimmunotherapy in this trial, 44% of the patients required a second line of therapy. Somehow, we are also reducing the risk of needing second therapies in these patients, which is also important because in second therapy, we are adding more toxicities, and with conventional chemoimmunotherapy, we are really seeing that most of the patients already require a second-line of therapy.