COPIKTRA (duvélisib)

Key points

Unfavourable opinion for reimbursement in the treatment of adult patients with relapsed or refractory chronic lymphocytic leukaemia (CLL) after at least two prior therapies and follicular lymphoma (FL) that is refractory to at least two prior systemic therapies.

Role in the care pathway?

• Relapsed or refractory chronic lymphocytic leukaemia (CLL)

According to the guidelines, the therapeutic indications are defined on the basis of the presence of symptoms and progression of the disease (in accordance with the existing Binet and Rai classifications).

In routine practice, patients with asymptomatic early-stage disease (Rai 0, Binet A) should be monitored without therapy unless they have evidence of disease progression or disease-related symptoms.

In patients requiring treatment, the choice of first-line therapy depends on several parameters: the patient’s age and general condition, the presence or otherwise of comorbidities and the cytogenetic status (presence of the (del)17p deletion and/or the TP53 mutation, IgVH mutation status):

- In the presence of a TP53 mutation and/or a (del)17p deletion:

                 * IMBRUVICA (ibrutinib) as monotherapy, currently the reference treatment,

                  * CALQENCE (acalabrutinib) as monotherapy or in combination with obinutuzumab

- In the absence of a TP53 mutation and/or a (del)17p deletion:

* In patients without significant comorbidities, the Transparency Committee estimated that the therapeutic strategy should be adapted on the basis of the patient’s IgVH mutation status:

 In patients with a mutated IgVH status, the treatment options that can be discussed are immunochemotherapy with rituximab + fludarabine + cyclophosphamide (FCR protocol) and targeted therapy with the IMBRUVICA (ibrutinib) + rituximab combination.

 In the event of a non-mutated IgVH status (currently recognised as being a factor for a poor response to immunochemotherapy), the IMBRUVICA (ibrutinib) + rituximab combination is the first-line treatment.

 It should be noted, however, that in France, IMBRUVICA (ibrutinib) as monotherapy does not currently have a reimbursed indication for the first-line treatment of patients eligible for the FCR protocol and not presenting a TP53 mutation or (del)17p deletion.

* In elderly patients and/or those with comorbidities making them ineligible for “full-dose” standard FCR protocols, the options are as follows:

 Anti-CD20 monoclonal antibody and chemotherapy combinations: GAZYVARO (obinutuzumab) + chlorambucil (G-Clb protocol), MABTHERA (rituximab) + bendamustine (BR)

 Targeted therapies: VENCLYXTO (venetoclax) + GAZYVARO (obinutuzumab) (G-VEN)

 IMBRUVICA (ibrutinib) as monotherapy.

 Acalabrutinib (CALQUENCE) in combination with obinutuzumab.

In relapsed or refractory patients, the initiation of a second-line treatment is based on the same criteria as those used for first-line therapy. The choice of treatment depends on several factors, such as comorbidities, the existence of a 17p mutation and/or TP53 mutation (to be tested for again), the nature of prior treatment(s) and the duration of the previous response. According to the guidelines, second and later-line therapies are preferentially based on the following treatment options:

- ibrutinib (IMBRUVICA);

- idelalisib (ZYDELIG) in combination with rituximab;

- venetoclax alone or in combination with rituximab, only as salvage therapy in CLL with 17p deletion or TP53 mutation in patients not having responded to a B cell antigen receptor inhibitor (second and later-line treatment), and without 17p deletion or TP53 mutation in patients not having responded to either immunochemotherapy or a B cell antigen receptor inhibitor (third and later-line treatment);

- acalabrutinib (CALQUENCE) as monotherapy, only in patients with no 17p deletion or TP53 mutation.

It should be noted that immunochemotherapy (in the absence of 17p deletion/TP53 mutation) as well as alemtuzumab, are second or later-line treatment options. However, the role of alemtuzumab (available as a compassionate use programme (CUP)) is marginal.

Role of the medicinal product in the care pathway:

Considering:

- demonstration of a superiority of duvelisib as monotherapy compared to a comparator, ofatumumab, considered not to be relevant on the date of this opinion, in the phase 3 DUO study, with, in addition:

                 * a modest improvement in terms of progression-free survival (primary endpoint; 13.3 months vs 9.9 months; HR = 0.52; 95% CI [0.39; 0.69]) and overall response rate (ranked secondary endpoints; 73.8% vs 45.3%; OR = 3.50, only one complete response),

                 * the absence of any demonstrated superiority in terms of overall survival, considered to be the most clinically relevant endpoint at this stage of the disease,

                  * and in the absence of a possible conclusion with respect to the quality of life results (exploratory endpoint);

- The transposability of the results to clinical practice that cannot be guaranteed given:

* the exclusion of patients having had prior treatment with a tyrosine kinase inhibitor or bcl-2 inhibitor, considered to be the standard of care therapies at this stage of the disease,

* the inclusion of patients receiving second-line therapy whereas the MA was only validated from the third line of treatment (60% of study patients, exploratory post hoc analyses in subgroups);

- Worrying safety data, marked primarily by diarrhoea/colitis, neutropenia and infectious events, with high proportions of adverse events considered to be serious (72.8% vs 32.3%), having led to treatment discontinuation (36.0% vs 5.8%) and sometimes death (12.0% vs 4.5%), compared to the ofatumumab group;

The Committee considers that COPIKTRA (duvelisib) has no role in the care pathway for adult patients with relapsed or refractory chronic lymphocytic leukaemia (CLL) after at least two prior therapies

• Refractory follicular lymphoma (FL)

As first-line therapy and in accordance with national and international guidelines, the treatment options are based on immunochemotherapy, i.e. a rituximab + chemotherapy (mainly R-CHOP, R-CVP or R-bendamustine) combination, followed by maintenance therapy with rituximab. In certain cases, treatment with rituximab as monotherapy may be recommended (off-label). As an alternative to rituximab, obinutuzumab (GAZYVARO) may also be used as induction therapy in combination with chemotherapy (mainly CHOP, CVP or bendamustine), followed by maintenance therapy with obinutuzumab.

In the event of non-response or progression, a second-line protocol is proposed. A new tumour sample biopsy, potentially PET-scan guided, is recommended, in order to eliminate transformation to diffuse large B-cell lymphoma. The second-line treatment depends on the first-line therapy received, the type and duration of the remission previously obtained and the spread of the disease. The second-line treatments are based on:

- a new immunochemotherapy protocol (R-CHOP, R-CVP, R-bendamustine, O-bendamustine),

- or radio-immunotherapy if the degree of bone marrow involvement allows,

- and/or stem cell transplantation if the patient’s age allows and, in particular, in the event of early relapse

In patients non-refractory to rituximab, in situations in which CHOP, bendamustine or CVP chemotherapy is not possible, lenalidomide (REVLIMID) may be used in combination with rituximab.

From the third line of treatment, idelalisib (ZYDELIG) may be proposed, along with treatments used as second-line therapy.

Role of the medicinal product in the care pathway:

Considering:

- the results of the phase 2 non comparative DYNAMO study conducted in patients with non-Hodgkin lymphoma, including 60% with follicular lymphoma corresponding to the MA, with a modest improvement in terms of overall response rate (42.2% including only one complete response), primary endpoint not considered to be relevant at this stage of the disease;

- the absence of comparison with the currently available treatments, despite this being feasible;

- worrying safety data, in line with the data found in the CLL indication and with other PI3K inhibitors;

The Committee considers that COPIKTRA (duvelisib) has no role in the care pathway for patients with chronic lymphocytic leukaemia (CLL) refractory to at least two prior therapies.