The CLL17 trial was focussed on patients with previously untreated CLL who were randomised to three different treatment approaches. The overarching question in this clinical trial was how fixed-duration treatment options compare to continuous treatment in CLL since these two treatment principles have so far been only developed and compared to chemo and chemoimmunotherapy but we don’t know how these treatment approaches compare to each other. So the CLL17 trial randomised patients with previously untreated CLL to receive the three main contemporary treatment regimens that exist in CLL, that is continuous BTK inhibition with ibrutinib, fixed-duration venetoclax/obinutuzumab administered over approximately a year, or fixed-duration venetoclax/ibrutinib also administered over approximately a year.

What was the study design?

So this study was designed as a non-inferiority trial because we want to test and confirm that a shorter therapy is clinically equally effective to a long-term indefinite therapy. So we therefore hypothesised that venetoclax/obinutuzumab would be non-inferior to continuous ibrutinib in terms of progression free survival. The second hypothesis was that fixed-duration venetoclax/ibrutinib is non-inferior to continuous ibrutinib in terms of progression free survival.

What were the key results?

The main finding in this clinical trial relates, of course, to the primary endpoint where we did observe after a median observation of approximately three years that, indeed, the fixed duration options are both non-inferior to continuous ibrutinib. So in all three arms we had three-year PFS rates of approximately 80% across all the three arms, thereby in this first readout of the study confirming the hypothesis of clinical equal efficacy of fixed duration treatment compared to continuous treatment.

What is the key takeaway from comparing fixed-duration therapy with continuous treatment in the CLL17 trial?

In clinical terms the findings mean that for most patients with previously untreated CLL we should consider limited-duration strategies as a primary option. We did see that the non-inferiority or clinical efficacy, or equal clinical efficacy, were maintained in most subgroups we looked at. So also in unmutated IGHV status and intermediate adverse risk factors, we saw that the fixed-duration options were non-inferior to continuous ibrutinib. So this already represents over 60% of the patient population in treatment-naïve contexts. However, there are still some subgroups like the TP53 altered subgroup or the complex karyotype subgroup where we notice that there might be trends that fixed-duration options have a bit more limited efficacy there than the continuous treatments. On the other hand, we did notice that especially the BTKI-containing regimens showed clear efficacy also in a fixed-duration context in the context of high risk disease. But these smaller high-risk subgroups require longer observation time and more events to be more statistically certain about possible superiority or non-inferiority.

What is the clinical significance of these results?

The clinical significance is really that since most patients were represented in this clinical trial, with over 900 patients, we were able to really enrol an all-comer first-line patient population that included patients with high-risk disease but also patients who would be considered clinically unfit due to co-existing conditions. These represented over 40% of the enrolled patients. So we can therefore have a really robust dataset that represents the typical CLL patient population seen in routine clinical care and, therefore, based on the findings be guided into which treatment approach to choose.

Again, the data both in terms of the toxicity profiles and the efficacy profiles really suggest that limited-duration strategies should be a preferable option, given that they mean clinical equal efficacy whilst having a substantially shorter duration of treatment which is very valuable for patients since this is the only way to provide them with treatment-free intervals whilst having active disease control.