Optimal 2nd-Line Treatment for CLL? GAIA/CLL13 Findings | Carsten Niemann, MD

Hi, I'm Karsten Uthoff-Niemann. I'm a haematologist from Copenhagen, Denmark, and I'm chairing the Nordic CLL Study Group, and I'm happy to be here at the AASP meeting this year. So the GAIA CLL13 trial is an investigator-initiated trial sponsored by the German CLL Study Group, developed in collaboration with the Nordic CLL Study Group and the Hohen Group, testing frontline treatment for patients with CLL. First, starting out with chemoimmunotherapy, then exchanging the chemotherapy backbone with venetoclax, and next, changing the immune therapy in terms of CD20 monoclonals to OB-notucimab, and finally adding ibrutinib for triplet arm. So these results have been published and presented earlier on the outcome from the first line setting. But as we've got such good treatment options for patients with CLL today, we need now to test what is the optimal sequence of next-line treatment. And as we were so happy in the GAIA CLL13 trial to collect information also on next-line treatment outcomes, we are now at this year's AASP meeting, presenting data on 177 patients receiving second-line treatment for CLL after receiving one of the four treatment arms for the first-line treatment in the GAIA CLL13 trial. So this reflects also to me the importance of continued follow-up and long-term follow-up, not just from investigator-initiated trials, but also from pharma company-sponsored trials. So important that we actually get this information because we have succeeded to improve the treatment outcomes in CLL so much. So what we find in this final report on the GAIA CLL13 trial, looking into the outcome for next-line treatment, is that if you have received venetoclax-based treatment in the front-line setting, that could be venetoclaxotoxamab, venetoclaxobinotuzumab, or the triplet of venetoclaxobinotuzumab by Brutib, then it's effective to re-treat with a venetoclax-based treatment regimen in the next line. We have looked at four different major classes of drugs used in the second line, and it's important to remember that this is not a randomized next line. It's the physician, the PI's decision, together with the patient, what they provided as next-line treatment. We just collect the outcome. We can see very clearly that chemoimmunotherapy, even after venetoclax-based first-line treatments, thus patients who never received chemoimmunotherapy, is not a good choice. It has much shorter duration of response than any of the targeted options. Then we had ibrutinib or BTK inhibitor-based next-line treatment, or we had venetoclax-based next-line treatment that could be in combination with a CD20 monoclonal usually, and then we had patients receiving a BTK inhibitor together with venetoclax. So three different targeted approaches either based on a BTK inhibitor, based on venetoclax, or based on the combination of a BTK inhibitor and venetoclax. And we saw that all three options provided good and long-lasting responses after next-line treatment. And this is really informing us about what would be the optimal treatment trajectory for a patient with CLL, because also at this ASP meeting we are presenting the first analysis of the CLL17 trial, combining indefinite BTK inhibitor to a BTK inhibitor together with venetoclax or to venetoclax or binotuzumab. And that trial is shown, it was a trial designed for non-inferiority, that the time-defined treatment in the front-line setting is non-inferior, so as good as continuous BTK inhibitor, with the caveat that it's the first analysis from this trial, only a three-year median follow-up. And now from the Gaia CLL13 trial we can further inform that it's feasible to retreat the patients who received the venetoclax-based time-defined treatment in the front-line setting, we can invite them in for next-line treatment. Thus, even though we compare it to continuous treatment with a BTK inhibitor, we can now see that we might lower the toxicity while still providing us good or even better outcomes for the patients, because we can retreat with the same combination. And we achieved a two-year progression-free survival above 80-90 percent with the retreatment in the Gaia CLL13 trial with the venetoclax-based combinations. What we need to consider now in CLL when we have patients receiving multiple lines of treatment, are actually based on this good outcome. When we look at Danish registry data, real-world data, we can see that even for the patients up to around 60 years of age, whether they have high-risk CLL disease or low-risk CLL disease, their five-year overall survival is exactly the same and very close to, if not equal to, the background population. So it's all about the very long time perspective for patients with CLL, except for if we have very elderly, frail patients. Thus, we really need to consider not just the frontline treatment, but the sequential treatment lines. And here we need the long-term follow-up, which we provide here from the Gaia CLL13 trial, to address how you best combine different lines of treatment. And what we see here is that in the Gaia CLL13 trial, we have venetoclax-retoxamab, venetoclax-obinotuzumab, or the triplet, including ibrutinib also. And now in second-line treatment, even though it's not powered, it's just a descriptive analysis, it looks like combining a venetoclax with a BTK inhibitor in the next-line treatment gives the optimal outcomes. So it makes sense that if you started out treating with a venetoclax combined with a CD20 monoclonal, then the next-line treatment would optimal have a different partner. And that's what we can actually see gives very long, durable responses for these patients. But that brings us to a problem because venetoclax ibrutinib and also venetoclax acala ibrutinib has been approved in the frontline setting, but those have not been tested in registration trials in the second-line and later-line treatment. But now we can see that this is actually an optimal way to sequence treatment, either starting with a venetoclax and a CD20 monoclonal, here obinotuzumab, or starting with venetoclax and a BTK inhibitor, ibrutinib, acala ibrutinib, and then switching in the next-line treatment to venetoclax with the other combining partner. But that means that we need to change the approval process to actually get approval for these different treatment options, venetoclax for obinotuzumab and venetoclax with a BTK inhibitor both in the frontline setting and the second-line setting.