Analyst Notes: Targeted therapy combinations set to take centre stage in CLL

Chronic lymphocytic leukaemia (CLL) primarily occurs in elderly patients (median age of diagnosis is 72 years) and represents approximately 30 percent of all diagnosed leukaemia cases in the US. Compared to other acute leukaemias, the prognosis of CLL is relatively good with an average five-year survival rate of 80 percent in Western countries. Like most oncology indications, chemotherapy has dominated the CLL treatment landscape and chemo-immunotherapy regimens incorporating Roche's anti-CD20 agents Rituxan/MabThera (rituximab) or Gazyva/Gazyvaro (obinutuzumab) have been gold standard treatment. However, the past five years have witnessed a shift in the treatment paradigm towards oral targeted therapies. In particular, the approval of three key brands – Johnson & Johnson/AbbVie's Imbruvica (ibrutinib), Gilead Sciences' Zydelig (idelalisib) and AbbVie/Roche's Venclexta/Venclyxto (venetoclax) – has resulted in a move away from conventional chemotherapy-based regimens.

Insights, Analysis & Opinion

Traditionally, the standard first-line treatment for the majority of 'fit' patients with CLL are intensive chemo-immunotherapy regimens consisting of fludarabine, cyclophosphamide and Rituxan (FCR) or bendamustine and Rituxan (BR). However, numerous Phase III studies are ongoing at present evaluating novel doublet and triplet combinations of Imbruvica or Venclexta/Venclyxto with anti-CD20 agents compared to these traditional regimens in the front-line setting.

"For the younger patients, I really see the combinations going forward, and I think there will be a venetoclax-based [combination]; they will incorporate a CD20 antibody and perhaps a BTK inhibitor as well. I really see the kinase inhibitors taking over patients in first-line, and venetoclax really being a mainstay in younger patients." - US Key Opinion Leader

Key opinion leaders (KOLs) interviewed by FirstWord for a recent report, KOL Insight: Chronic Lymphocytic Leukaemia (CLL), are optimistic about the oral targeted combinations and foresee them beginning to gradually dominate the market. They are particularly excited about the front-line doublet combination of Imbruvica with anti-CD20 therapies, and the front-line triplet combination of Venclexta/Venclyxto with Gazyva and Imbruvica. With the combination studies still ongoing, it remains to be seen which combination will ultimately be superior.

KOLs stress that any novel first-line combinations will need to demonstrate superiority over conventional regimens (e.g. FCR or BR) to gain uptake in the young fit patient subgroup. However, they stress that chemo-immunotherapy will continue to be utilised in younger patients with mutated immunoglobulin heavy chain variable (IgVH) genes due to its proven long-term clinical benefit within this subgroup. KOLs are also hopeful about the potential to achieve deeper remissions (minimal residual disease [MRD]-negativity) as this may provide an opportunity to shorten the duration of treatment, which is already considered lengthy and expensive.

The experts confirm that the CLL treatment landscape is set to undergo a transformation over the next five years as new therapies enter the market and new combinations of existing agents are approved. The most striking change will come from a move away from traditional regimens to combinations of oral targeted agents and KOLs expect this shift to be fuelled by the recent expansion of Imbruvica monotherapy to the front-line setting across all patient subgroups.

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