30 mei 2010: bron: The Lancet en Medscape

Tarceva en Iressa, zogeheten EGRF remmers geven significant levensverlenging bij patienten met inoperabele longkanker. Echter bij longkankerpatienten met bepaalde tumorreceptoren en bepaalde mutaties was het effect heel veel beter dan algemeen. Dit toont een grote placebo gecontroleerde fase III studie aan (Saturn studie) en werd gepubliceerd in The Lancet afgelopen week.

De resultaten tonen aan dat, vergeleken met placebo, erlotinib (Tarceva,) aanzienlijk de progressie-vrije overleving verbetert. (hazard ratio , 0,71; mediaan, 12,3 versus 11,1 weken) en algehele mediane overleving (HR 0,81; mediaan, 12,0 vs 11,0 maanden) bij patiënten met gevorderde niet-klein-cellige longkanker (NSCLC).

De beste effecten met erlotinib werden gezien in een kleine subgroep van de patiënten in de studie - die met een epidermale groei factor receptor (EGFR) mutatie - maar deze patiënten waren goed voor slechts 22 van de 438 (5%) met Tarceva - erlotinib behandelde patiënten. Dat maakt ook dat juist wie de juiste receptoren en mutaties heeft hier van kan profiteren

"Erlotinib werd in verband gebracht met een ongekende hazard ratio van 0,10 (P <0,0001) voor patiënten met een EGFR mutatie," aldus Thomas E. Stinchcombe, MD, en Suresh S. Ramalingam, MD, in een editoriaal dat de resultaten van de studie becommentarieerde .

Echter, dit ongekende resultaat voor progressie-vrije overleving lijkt zich niet te vertalen in een statistisch significante verbetering in de algemene overleving, waarschijnlijk omdat de meeste van de patiënten uit de placebogroep met een EGFR mutatie behandeling alsnog tarceva - erlotinib kregen als er progressie van de ziekte optrad, aldus Dr Stinchcombe, van de Universiteit van North Carolina in Chapel Hill, en Dr Ramalingam, van Emory University in Atlanta, Georgia.

Dit cross-over effect op totale overleving doet niets af aan de indrukwekkende verbetering van de progressievrije overleving bij patiënten met een EGFR mutatie - ook al is het een kleine, beperkte groep, aldus het commentaar in The Lancet

De bijwerkinge waren in de Tarcevagroep iets groter dan in de placebogroep maar niet heel ernstig en wel te behandelen:

In SATURN, the most common grade 3 or higher adverse events were rash (9% in the erlotinib group vs 0% in the placebo group) and diarrhea (2% vs 0%), report the study authors, led by Federico Cappuzzo, MD, from Ospedale Civile di Livorno in Italy.

Lancet Oncol. 2010 May 19. [Epub ahead of print]

Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study.

Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczésna A, Juhász E, Esteban E, Molinier O, Brugger W, Melezínek I, Klingelschmitt G, Klughammer B, Giaccone G; on behalf of the SATURN investigators.

Department of Medical Oncology, Ospedale Civile di Livorno, Livorno, Italy.

Abstract

BACKGROUND: First-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) is usually limited to four to six cycles. Maintenance therapy can delay progression and prolong survival. The oral epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor erlotinib has proven efficacy and tolerability in second-line NSCLC. We designed the phase 3, placebo-controlled Sequential Tarceva in Unresectable NSCLC (SATURN; BO18192) study to assess use of erlotinib as maintenance therapy in patients with non-progressive disease following first-line platinum-doublet chemotherapy.

METHODS: Between December, 2005, and May, 2008, 1949 patients were included in the run-in phase (four cycles of platinum-based chemotherapy). At the end of the run-in phase, 889 patients who did not have progressive disease were entered into the main study, and were randomly allocated using a 1:1 adaptive randomisation method through a third-party interactive voice response system to receive erlotinib (150 mg/day; n=438) or placebo (n=451) until progression or unacceptable toxicity. Patients were stratified by EGFR immunohistochemistry status, stage, Eastern Cooperative Oncology Group performance status, chemotherapy regimen, smoking history, and region. Co-primary endpoints were progression-free survival (PFS) in all analysable patients irrespective of EGFR status, and PFS in patients whose tumours had EGFR protein overexpression, as determined by immunohistochemistry. This study is registered with www.ClinicalTrials.gov, number NCT00556712.

FINDINGS: 884 patients were analysable for PFS; 437 in the erlotinib group and 447 in the placebo group. After a median follow-up of 11.4 months for the erlotinib group and 11.5 months for the placebo group, median PFS was significantly longer with erlotinib than with placebo: 12.3 weeks for patients in the erlotinib group versus 11.1 weeks for those in the placebo group (HR 0.71, 95% CI 0.62-0.82; p<0.0001). PFS was also significantly longer in patients with EGFR-positive immunohistochemistry who were treated with erlotinib (n=307) compared with EGFR-positive patients given placebo (n=311; median PFS 12.3 weeks in the erlotinib group vs 11.1 weeks in the placebo group; HR 0.69, 0.58-0.82; p<0.0001). The most common grade 3 or higher adverse events were rash (37 [9%] of 443 patients in the erlotinib group vs none of 445 in the placebo group) and diarrhoea (seven [2%] of 443 patients vs none of 445). Serious adverse events were reported in 47 patients (11%) on erlotinib compared with 34 patients (8%) on placebo. The most common serious adverse event was pneumonia (seven cases [2%] with erlotinib and four [<1%] with placebo).

INTERPRETATION: Maintenance therapy with erlotinib for patients with NSCLC is well tolerated and significantly prolongs PFS compared with placebo. First-line maintenance with erlotinib could be considered in patients who do not progress after four cycles of chemotherapy. FUNDING: F Hoffmann-La Roche Ltd. Copyright © 2010 Elsevier Ltd. All rights reserved.

PMID: 20493771 [PubMed - as supplied by publisher]

In Medscape werd ook dit nog geschreven voer longkankerpatienten met het wild type EGFR

Pemetrexed or Erlotinib for Patients With Wild-Type EGFR?

Maintenance therapy for NSCLC is defined as the use of an effective agent in the absence of disease progression following platinum-based combination chemotherapy, the editorialists explain.

An outstanding question for clinicians is whether or not erlotinib is the best choice for maintenance therapy in patients with wild-type EGFR.

Patients with wild-type EGFR accounted for 45% and 42% of the treatment and placebo groups, respectively, in the 889-patient SATURN trial.

But the trial results indicate that erlotinib was not highly effective in NSCLC patients with wild-type EGFR.

"The benefit of maintenance erlotinib compared with placebo in terms of progression-free survival and overall survival was modest for such patients," write Drs. Stinchcombe and Ramalingam, referring to the wild-type patients.

Pemetrexed is a better choice for maintenance therapy in patients with wild-type EGFR, suggest the editorialists.

Pemetrexed is "likely to be the preferred agent in patients with nonsquamous histology, based on the improvement in median survival of 5 months seen with pemetrexed compared with placebo," they opine, suggesting that patients with squamous cell carcinomas are unlikely to have the mutation.

The SATURN trial was funded by F. Hoffman-La Roche. Dr. Stinchcombe reports being on the speakers' bureau of Lilly and Genentech. Dr. Ramalingam reports working as a consultant for Genentech, Imclone, Syndax, Astellas, Amgen, and GlaxoSmithKline. Dr. Cappuzzo reports receiving honoraria from Roche, Eli-Lilly, AstraZeneca, and Boehringer; and receiving payment for development of educational presentations, including service on speakers' bureaus, from Roche, Eli-Lilly, AstraZeneca, and Boehringer.

Lancet Oncol. Published online May 20, 2010.

erlotinib, egfr, maintenance, nsclc, wild, saturn, wild-type, tarceva, mutatie, pemetrexed