Αρχική World News Results of Continuous vs Intermittent Dosing Schedules of BRAF/MEK Inhibitor Combination Therapy...

Results of Continuous vs Intermittent Dosing Schedules of BRAF/MEK Inhibitor Combination Therapy in the S1320 Study

Opposite to the initial study hypothesis, the results of the S1320 indicate that intermittent dosing of BRAF/MEK inhibitor combination did not improve progression-free survival (PFS) in patients with BRAF-mutated melanoma. There were no differences between the groups of patients who received continuous vs intermittent dosing schedules in terms of the secondary outcomes, including overall survival and the overall incidence of treatment-associated toxicity according Alain P. Algazi of the University of California in San Francisco, CA, USA and colleagues who published their findings on 5 October 2020 in the Nature Medicine.

Combination treatments with BRAF and MEK inhibitors yield objective response rates of up to 70% in patients with advanced BRAFV600 melanoma. However, acquired resistance, often driven by MAPK pathway reactivation is common problem. The authors wrote in the study background that preclinical modelling suggests that intermittent BRAF inhibitor therapy may delay acquired resistance when blocking oncogenic BRAFV600 in melanoma.

In particular, preclinical modelling demonstrated that BRAFV600E cells that had become resistant to the BRAF inhibitor vemurafenib in vitro grew poorly in the absence of the drug, and intermittent dosing of vemurafenib according to a 4-week-on, 2-week-off schedule prolonged drug sensitivity and increased PFS in a mouse model. The drug withdrawal effect is even more profound in BRAFV600 mutant cells with acquired resistance to BRAF and MEK inhibitor combinations.

Based on these findings, the study team prospectively tested whether intermittent therapy with combination of BRAF and MEK inhibitors improved PFS compared to standard daily continuous dosing of these agents. The S1320 is a randomised, open-label, phase II clinical trial (NCT02196181) that evaluated whether intermittent dosing of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib improves PFS in patients with metastatic and unresectable BRAFV600 melanoma.

Patients were enrolled at 68 academic and community sites in the US. All patients received continuous dabrafenib and trametinib during an 8-week lead-in period, after which patients with non-progressing tumours were randomised to either continuous or intermittent dosing of both drugs on a 3-week-off, 5-week-on schedule.

The S1320 focused on the effect of the dosing schedule on acquired resistance, randomising only patients benefiting from therapy after an 8-week lead-in period, during which all patients received continuous treatment. For those patients randomised to intermittent dosing, the off-treatment interval was extended to 3 weeks on the basis of pharmacokinetic modelling taking into account the longer plasma half-life of the combination of dabrafenib and trametinib in patients compared to the shorter plasma half-life of vemurafenib in mice, and the treatment cycle was extended to a total of 8 weeks to allow clinical imaging response assessments at standard 8-week intervals.

Between September 2014 and April 2019, 249 patients were registered to the first, lead-in dosing cycle of the study. Of these patients, 242 were found eligible to enrol and received study therapy, and 206 non-progressing patients were randomised: 105 to continuous and 101 to intermittent dosing.

A single interim analysis was performed on a data lock with follow-up as of 25 August 2017 after 74 events (progressions and deaths) had occurred. Using a stratified Cox regression model, the hazard ratio was 1.10 with a one-sided 95% confidence interval of 0.75, infinity and a one-sided p value of 0.33. The protocol called for early termination if the p value was less than 0.05, so the protocol met the criteria to continue.

At the final analysis, the randomised arms were well balanced.

Continuous dosing yielded a statistically significant improvement in post-randomisation PFS compared with intermittent dosing with median 9.0 months vs 5.5 months (p = 0.064, pre-specified two-sided α = 0.2).

The authors concluded that contrary to the initial hypothesis, the S1320 study comparing different dosing schedules of BRAF/MEK inhibitor combination in BRAF-mutated advanced melanoma showed that intermittent therapy does not result in superior PFS.

Reference

Algazi AP, Othus M, Daud AI, et al. Continuous versus intermittent BRAF and MEK inhibition in patients with BRAF-mutated melanoma: a randomized phase 2 trial. Nature Medicine 2020;26:1564-1568.

Source

NEWSLETTER

Συμπληρώστε το email σας για να λαμβάνετε τις σημαντικότερες ειδήσεις από το ogkologos.com

Βρείτε μας

2,449ΥποστηρικτέςΚάντε Like
57ΑκόλουθοιΑκολουθήστε

Διαβαστε Επίσης

Καρκίνος και Κορωνοϊός (COVID-19) ΜΕΡΟΣ Α

Εάν είστε καρκινοπαθής, το ανοσοποιητικό σας σύστημα μπορεί να μην είναι τόσο ισχυρό όσο κανονικά, έτσι μπορεί να ανησυχείτε για τους κινδύνους που σχετίζονται...

ΠΑΓΚΟΣΜΙΑ ΗΜΕΡΑ ΚΑΡΚΙΝΟΥ

Η Παγκόσμια Ημέρα Κατά του Καρκίνου καθιερώθηκε με πρωτοβουλία της Διεθνούς Ένωσης κατά του Καρκίνου (UICC), που εκπροσωπεί 800 οργανώσεις σε 155 χώρες του...

ΕΞΕΛΙΞΕΙΣ ΣΤΗ ΘΕΡΑΠΕΙΑ ΤΟΥ ΜΗ-ΜΙΚΡΟΚΥΤΤΑΡΙΚΟΥ ΚΑΡΚΙΝΟΥ ΤΟΥ ΠΝΕΥΜΟΝΑ (ΜΜΚΠ)

ΕΞΕΛΙΞΕΙΣ ΣΤΗ ΘΕΡΑΠΕΙΑ ΤΟΥ ΜΗ-ΜΙΚΡΟΚΥΤΤΑΡΙΚΟΥ ΚΑΡΚΙΝΟΥ ΤΟΥ ΠΝΕΥΜΟΝΑ (ΜΜΚΠ) Γράφει ο Δρ Παπαδούρης Σάββας, Παθόλογος-Ογκολόγος   Ο ΜΜΚΠ βρίσκεται αναλογικά στο 80% και πλέον του συνολικού...

Διατρέχουν όντως οι καρκινοπαθείς μεγαλύτερο κίνδυνο λόγω κοροναϊού;

Σε πρακτικό επίπεδο, τα δεδομένα των σχετικών μελετών υποδηλώνουν ότι η χημειοθεραπεία ή οι άλλες αντι-νεοπλασματικές θεραπείες δεν αυξάνουν σημαντικά τον κίνδυνο θνησιμότητας από...

FDA: Η ακτινοβολία των smartphones δεν προκαλεί καρκίνο

Σε μια νέα έκθεσή της, η Υπηρεσία Τροφίμων και Φαρμάκων (FDA) των ΗΠΑ αναφέρει ότι επανεξέτασε τις σχετικές επιστημονικές έρευνες που δημοσιεύθηκαν τα τελευταία...

Νέα ανακάλυψη, νέα ελπίδα για τον καρκίνο

Ένα νεοανακαλυφθέν τμήμα του ανοσοποιητικού μας συστήματος θα μπορούσε να αξιοποιηθεί για την αντιμετώπιση όλων των ειδών καρκίνου, σύμφωνα με επιστήμονες του πανεπιστημίου Cardiff...
- Advertisment -

Ροή Ειδήσεων

Overall Breast Cancer Incidence Down Since 1999, Rates Increase for Women Under 40

U.S. breast cancer death rates decreased by about 1% per year between 2013 and 2018. What were the new case rates during that same...

Impressive Responses to PD-1 Blockade in a Large Cohort of Children and Young Adults with Recurrent/Progressive Germline DNA Replication Repair-Deficient Cancers

A large, observational, registry-based study that leveraged systematically collected data gathered both retrospectively and prospectively through the International Replication Repair Deficiency Consortium reveals impressive...

2-Year-Boy Is So Excited To See Himself In Disney’s ‘Encanto’

The importance of representation in media has been a growing topic of concern, and companies have responded by adding more diversity to their characters,...

Man Walks Entire Continent To Spread Awareness About Mental Health & Suicide Prevention

Matthew Fennell is walking over 3,000 miles across Australia for an important cause and one that is near and dear to his heart. Last year,...

Boy Battling Cancer Becomes Honorary Police Officer, Sworn In To 45 Agencies

At just ten years old, Devarjaye “DJ” Daniel has already been through more than most people go through in their entire lives. DJ has been...

Paclitaxel and Carboplatin Not Inferior When Compared with Paclitaxel and Ifosfamide for the Treatment of Patients with Uterine Carcinosarcoma

With regard to overall survival (OS), paclitaxel and carboplatin was not inferior and demonstrated improved progression-free survival (PFS) when compared with paclitaxel and ifosfamide...