ELEVATE TN: Comparing acalabrutinib monotherapy or in combination with obinutuzumab in treatment-naïve CLL
Dr Jeff Sharman - Willamette Valley Cancer Institute and Research Center, Eugene, USA
The ELEVATE TN trial is a study of acalabrutinib in patients with untreated chronic lymphocytic leukaemia. The specifics of the study design are that this was a three arm study comparing the combination of obinutuzumab with acalabrutinib, acalabrutinib alone and chlorambucil obinutuzumab as the control arm. Suitable or eligible patients were aged 65 and above or less than age 65 with medical comorbidities for which a more intensive chemotherapy regimen would render them unsuitable. Patients who were on the control arm who experienced progression could then cross over to acalabrutinib monotherapy once there was confirmation of disease progression. The primary endpoint to the study was progression free survival for those individuals randomised to acalabrutinib with obinutuzumab versus those with chlorambucil obinutuzumab. Key secondary endpoints included the comparison of monotherapy to control as well. Additional secondary endpoints were safety, overall survival, time to next treatment and so forth.
With regards to the progression free survival we evaluated a two year landmark as the median was not reached in either of the acalabrutinib containing arms. So at the two year mark the combination of obinutuzumab and acalabrutinib had a 93% progression free survival. For those patients on acalabrutinib monotherapy it was 87% and for those individuals who received chlorambucil in combination with obinutuzumab the two year progression free survival was 47%. Overall survival was very similar between the arms, that was a secondary endpoint. The hazard ratio for progression free survival for patients treated with BTK with CD20 was 0.1 with a highly statistically significant p-value. For acalabrutinib monotherapy the hazard ratio was 0.2 also with a p-value of less than 0.0001. There was a post-hoc descriptive comparison between acalabrutinib with and without obinutuzumab. We did see a slight improvement in outcomes with obinutuzumab with regards to progression free survival, however, the study wasn’t powered to draw any firm conclusions about that benefit.
Some of the most common side effects observed were headache. Patients treated with acalabrutinib, approximately one-third of patients will have a headache. That headache generally occurs within the first few days of taking the medication, it tends to be self-limited and will resolve on its own. For some individuals extra hydration or caffeine can alleviate the symptoms. A few patients needed Tylenol or ibuprofen but for the most part this was relatively self-limited. Neutropenia was most commonly seen on the control arm. The lowest rate was seen in acalabrutinib monotherapy and the addition of CD20 did result in additional neutropenia.
Other safety features, adverse events of special interest, included bruising and bleeding. Bleeding was seen in approximately one-third of acalabrutinib treated patients, however, rates of severe bleeding were quite low, just a few percentage points. Hypertension appeared to be infrequent with acalabrutinib and few patients developed atrial fibrillation on the medication as well.
How should clinicians decide which regimen to use?
There are now two BTK inhibitors approved for the treatment of patients with chronic lymphocytic leukaemia. They have very similar overall approvals for the treatment of CLL, there aren’t necessarily subgroups that tell us. The two medications, in terms of their relative efficacy we don’t know yet. There is a randomised phase III study that is ongoing that is directly comparing the safety and efficacy of the two BTK inhibitors. Results from that should be available sometime in the next few years, it’s still a ways off. That will give us the most definitive answer. In the meantime we have cross-trial comparisons which have limitations but it would appear that individuals treated with acalabrutinib may have less arthralgias and myalgias than acalabrutinib, similarly there appears to be less cardiac toxicity with lower rates of hypertension and atrial fibrillation. There are similar rates, however, of bruising and bleeding, at least numerically. Whether or not those change once we have randomised head-to-head data we’ll be in a better position to know.