New fixed-duration therapy could reshape CLL care

Advances in haematology drug discovery have led to targeted therapies that disrupt cancer pathways with greater precision than traditional chemotherapy. In chronic lymphocytic leukaemia (CLL), breakthroughs like acalabrutinib (Calquence) and venetoclax have been designed to block key survival mechanisms in cancer cells, offering more effective and less toxic treatment options.

Benjamin Moutier, now Senior Vice President of Vaccines and Immune Therapies at AstraZeneca, previously served as Vice President and Global Franchise Head of Hematology. He recently discussed the AMPLIFY Phase III trial, which builds on existing research to evaluate new therapies as a potential first-line standard of care, aiming to improve outcomes and reduce treatment burden.

The AMPLIFY trial: a paradigm shift in CLL treatment

The AMPLIFY trial, a global, multi-centre, open-label Phase III study, has sparked significant interest in the haematology community. It assessed the efficacy and safety of acalabrutinib (Calquence) combined with venetoclax, with or without obinutuzumab, compared to standard chemoimmunotherapy in 867 adults with previously untreated CLL. The findings, presented at ASH 2024 and published in the New England Journal of Medicine, have the potential to redefine first-line treatment for this chronic disease.

“AMPLIFY is a randomised, global, multi-centre, open-label, Phase III trial evaluating the efficacy and safety of acalabrutinib in combination with venetoclax (Arm A) and acalabrutinib in combination with venetoclax with or without obinutuzumab (Arm B) compared to chemoimmunotherapy (fludarabine, cyclophosphamide and rituximab, or bendamustine and rituximab) (Arm C) in adult patients (n=867) with previously untreated CLL,” Moutier explained.

The study’s primary endpoint was progression-free survival (PFS) and the results were striking. For patients treated with Calquence plus venetoclax, 76.5 percent were progression-free at three years, compared to 66.5 percent of patients treated with chemoimmunotherapy. This translates to a 35 percent reduction in the risk of disease progression or death. Even more impressive were the results for the Calquence plus venetoclax and obinutuzumab arm, where 83.1 percent of patients were progression-free at three years, representing a 58 percent reduction in the risk of disease progression or death.

Calquence plus venetoclax: a new standard of care

Moutier highlighted the importance of these findings, not only in terms of improved efficacy but also in their practical benefits. He noted the advantages of the regimen, stating, “Calquence plus venetoclax is an all-oral, fixed-duration regimen, compared to chemoimmunotherapy which is traditionally not, providing patients and physicians a new option to make the best treatment decision for each individual.”

The all-oral administration and fixed duration offer significant benefits over traditional chemotherapy, which often requires hospital visits for infusions and can be associated with significant side effects. The fixed-duration aspect of the Calquence plus venetoclax regimen also allows patients to complete a defined course of treatment and then have a break from therapy.

This is significant for drug discovery and early-stage therapeutics as it reflects a broader shift towards developing more precise, patient-friendly treatments. The success of Calquence plus venetoclax demonstrates the potential of targeted, mechanism-based therapies to improve outcomes while reducing treatment burden. The move towards an all-oral, fixed-duration regimen aligns with the growing emphasis on convenience, quality of life, and minimising long-term toxicity – key considerations in modern drug development. Additionally, these findings reinforce the value of rational drug design, where compounds are developed to selectively disrupt cancer pathways while limiting collateral damage to healthy cells. This approach not only enhances patient outcomes but also informs the future of early-stage therapeutic research, guiding the development of next-generation cancer treatments.

The advantages of fixed-duration treatment

CLL is a chronic disease, and patients often live with it for many years. Traditionally, treatment has been continuous, which can lead to cumulative toxicity – a constant burden for patients. Moutier explained the advantages of a fixed-duration approach. “Fixed-duration treatment regimens can allow those living with this chronic disease to take breaks from their treatment regimen. This both decreases the possibility of adverse events and drug toxicity and gives patients time off treatment where they can be relieved from experiencing side effects and from the mental load of thinking about their disease and treatment.”

This ‘treatment-free’ interval can significantly improve a patient’s quality of life, allowing them to focus on other aspects of their lives without the constant reminder of their illness and the associated side effects of ongoing treatment.

Reshaping first-line CLL treatment

Moutier believes that this combination fixed-duration therapy could become a new standard of care. “Calquence plus venetoclax fixed-duration therapy represents a potential new standard of care for patients in first-line CLL, in addition to the already approved option of continuous Calquence monotherapy. The AMPLIFY data demonstrated comparable efficacy to the ELEVATE-TN Phase III trial, evaluating Calquence monotherapy in CLL and a good safety profile, especially when looking at cardiac toxicity.”

This is key in drug development as it emphasises the shift towards personalised, targeted treatments. Furthermore, by providing finite treatment durations, it reduces the long-term side effects common in continuous therapies, aligning with the growing focus on precision medicine. The strong safety profile and efficacy shown in the AMPLIFY trial further highlight the importance of developing treatments that maximise patient outcomes while minimising harm.

He further emphasised the unique position of Calquence. “If approved based on these results, Calquence would be the only second-generation BTKi available in the first-line setting as both a treat-to-progression and finite treatment option, empowering patients and their healthcare providers with more options to make the best treatment decision for each individual.” Bruton’s tyrosine kinase inhibitor (BTKi) is a class of drugs that blocks the enzyme BTK, which is crucial for the survival of B cells.

The role of obinutuzumab

The AMPLIFY trial also explored the addition of obinutuzumab to the Calquence and venetoclax combination. Moutier explained the rationale behind this approach. “Obinutuzumab can be added to the Calquence regimen, as it provides an additional mechanism of action by which to target the disease. The results from AMPLIFY suggest that while the addition of obinutuzumab can result in higher efficacy and stronger responses, this does have to be balanced with an increase in adverse events.”

Thus, while the three-drug combination demonstrated the highest PFS rates, it also came with a higher risk of side effects. This highlights the importance of personalised medicine, where treatment decisions are made on an individual basis, considering the patient’s specific circumstances and risk tolerance.

Implications for the future of CLL care

The findings from the trial are a significant step forwards in the treatment of CLL. Moutier believes they will have a lasting impact on how CLL is managed. “These findings provide evidence for a potential new fixed-duration treatment approach in first-line CLL, adding a new option for patients living with this chronic cancer.”

In the context of early-stage drug discovery, the AMPLIFY trial highlights the ongoing evolution of cancer treatments towards more precise, patient-centric therapies. The potential of Calquence plus venetoclax as a fixed-duration, targeted regimen signals a shift in how chronic diseases like CLL are approached – focusing on reducing the treatment burden while enhancing efficacy. By offering a finite, all-oral therapy, the trial reflects the growing trend in drug development to create treatments that not only address the underlying disease mechanisms but also improve patient quality of life. This represents a significant milestone in the progression of personalised medicine, with therapies increasingly tailored to the specific needs of patients. It marks an important step towards developing the next generation of cancer treatments that are not only more effective but also easier for patients to manage.