1 januari 2022: Raadpleeg ook literatuurlijst niet-toxische middelen, voeding en weinig belastende behandelingen specifiek bij lymfklierkanker geselecteerd uit algemene literatuurlijst van arts-bioloog drs. Engelbert Valstar

1 januari 2022: Bron: The Lancet: Published:April 10, 2021

Uit de gerandomiseerde fase III CHRONOS-3 studie blijkt dat wanneer lymklierkankerpatiënten met het type indolent non-hodgkinlymfoom (NHL) bij een recidief of bij gevorderde ziekte na twee chemokuren de PI3K-remmer copanlisib gecombineerd met rituximab krijgen dan verminderde het risico op progressie of overlijden met 48%, vergeleken met een placebo plus rituximab.  

De PI3K-remmer copanlisib is goedgekeurd als monotherapie bij patiënten met recidiverend folliculair lymfoom (FL) die ten minste twee eerdere systemische therapieën hebben ondergaan.

In de CHRONOS-3-studie vergeleken onderzoekers de resultaten met rituximab met copanlisib of placebo bij 358 patiënten met recidiverend indolente NHL die gedurende ten minste 12 maanden progressievrij en behandelingsvrij waren sinds de laatste op rituximab gebaseerde therapie of die niet bereid/ongeschikt waren om chemotherapie krijgen.

De deelnemers werden 2:1 gerandomiseerd om ofwel:
copanlisib 60 mg op dag 1, 8 en 15 plus rituximab 375 mg/m2 op dag 1, 8, 15 en 22 tijdens cyclus 1 en op dag 1 van cycli 3, 5, 7 en 9 (n=307) placebo plus rituximab (n=151)
De mediane leeftijd van de patiënten was 63 jaar (bereik = 28-91).
FL was het meest voorkomende lymfoomhistologiesubtype (60%), gevolgd door marginale zonelymfoom (MZL; 20,7%), klein lymfocytisch lymfoom (SLL; 10,9%) en Waldenstrüm macroglobulinemie (WM; 8,3%).

De studie bereikte zijn primaire eindpunt na een mediane follow-up van 19,2 maanden, waarbij de copanlisib-combinatie een significant langere ziekteprogressievrije ziekte (PFS) vertoonde in vergelijking met de placebogroep (21,5 vs. 13,8 maanden; hazard ratio = 0,52; 95% BI 0,39- 0,69; p<0,001).

Het PFS-voordeel werd waargenomen bij alle histologische subtypes:
FL: HR=0.580MZL: HR=0.475SLL: HR=0,243WM: HR=0.443

De responspercentages (CR = complete remissies en PR = gedeeltelijke remissies) waren ook hoger in de copanlisib-groep dan in de placebogroep, aldus de auteurs.

De totale responspercentages (ORR's) waren respectievelijk 80,8% versus 47,7%, en de complete responspercentages (CRR's) waren 33,9% versus 14,6%. Opnieuw werden hogere ORR's en CRR's gezien bij alle indolente NHL-subtypes met behandeling met copanlisib plus rituximab.

De meest voorkomende tijdens de behandeling optredende bijwerkingen (AE's) bij patiënten die copanlisib kregen, waren:
hyperglykemie (alle gradaties: 69,4%; graad ‰¥3: 56,4%), 
hypertensie (49,2%; 39,7%) en diarree (33,6%; 4,9). %).

In de placebogroep waren de meest voorkomende bijwerkingen hyperglykemie (23,3%/8,2%), hypertensie (19,2%/8,9%), neutropenie (16,4%/12,3%) en infectie van de bovenste luchtwegen (16,4%/0%). Dr. Matasar, onderzoeksleider, merkte op dat in de copanlisib-groep zeer weinig patiënten moesten stoppen met de behandeling vanwege deze bijwerkingen. Longontsteking was een bijwerking waar de onderzoekers specifiek opletten, maar werd gemeld bij slechts 3% van de patiënten die copanlisib plus rituximab kregen.

Bij zes patiënten die copanlisib kregen en bij één patiënt die placebo kreeg, traden tijdens de behandeling optredende bijwerkingen van graad 5 op. Eén overlijden (pneumonitis) werd gemeld als geneesmiddelgerelateerd in de groep met copanlisib plus rituximab.

Het volledige studieverslag is in The Lancet gratis in te zien als u zich registreerd. Klik op de titel van het abstract:

ARTICLES| VOLUME 22, ISSUE 5P678-689, MAY 01, 2021

Copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (CHRONOS-3): a double-blind, randomised, placebo-controlled, phase 3 trial

 

Summary

Background

Copanlisib, an intravenous pan-class I PI3K inhibitor, showed efficacy and safety as monotherapy in patients with relapsed or refractory indolent non-Hodgkin lymphoma who had received at least two therapies. The CHRONOS-3 study aimed to assess the efficacy and safety of copanlisib plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma.

Methods

CHRONOS-3 was a multicentre, double-blind, randomised, placebo-controlled, phase 3 study in 186 academic medical centres across Asia, Australia, Europe, New Zealand, North America, Russia, South Africa, and South America. Patients aged 18 years and older with an Eastern Cooperative Oncology Group performance status of no more than 2 and histologically confirmed CD20-positive indolent B-cell lymphoma relapsed after the last anti-CD20 monoclonal antibody-containing therapy and progression-free and treatment-free for at least 12 months, or at least 6 months for patients unwilling or unfit to receive chemotherapy, were randomly assigned (2:1) with an interactive voice-web response system via block randomisation (block size of six) to copanlisib (60 mg given as a 1-h intravenous infusion on an intermittent schedule on days 1, 8, and 15 [28-day cycle]) plus rituximab (375 mg/m2 given intravenously weekly on days 1, 8, 15, and 22 during cycle 1 and day 1 of cycles 3, 5, 7, and 9) or placebo plus rituximab, stratified on the basis of histology, progression-free and treatment-free interval, presence of bulky disease, and previous treatment with PI3K inhibitors. The primary outcome was progression-free survival in the full analysis set (all randomised patients) by masked central review. Safety was assessed in all patients who received at least one dose of any study drug. This study is registered with ClinicalTrials.govNCT02367040 and is ongoing.

Findings

Between Aug 3, 2015, and Dec 17, 2019, 652 patients were screened for eligibility. 307 of 458 patients were randomly assigned to copanlisib plus rituximab and 151 patients were randomly assigned to placebo plus rituximab. With a median follow-up of 19·2 months (IQR 7·4–28·8) and 205 total events, copanlisib plus rituximab showed a statistically and clinically significant improvement in progression-free survival versus placebo plus rituximab; median progression-free survival 21·5 months (95% CI 17·8–33·0) versus 13·8 months (10·2–17·5; hazard ratio 0·52 [95% CI 0·39–0·69]; p<0·0001). The most common grade 3–4 adverse events were hyperglycaemia (173 [56%] of 307 patients in the copanlisib plus rituximab group vs 12 [8%] of 146 in the placebo plus rituximab group) and hypertension (122 [40%] vs 13 [9%]). Serious treatment-emergent adverse events were reported in 145 (47%) of 307 patients receiving copanlisib plus rituximab and 27 (18%) of 146 patients receiving placebo plus rituximab. One (<1%) drug-related death (pneumonitis) occurred in the copanlisib plus rituximab group and none occurred in the placebo plus rituximab group.

Interpretation

Copanlisib plus rituximab improved progression-free survival in patients with relapsed indolent non-Hodgkin lymphoma compared with placebo plus rituximab. To our knowledge, copanlisib is the first PI3K inhibitor to be safely combined with rituximab and the first to show broad and superior efficacy in combination with rituximab in patients with relapsed indolent non-Hodgkin lymphoma.

Funding

Bayer.

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