Immuuntherapie met Atezolizumab naast een gerichte behandeling met vemurafenib + cobimetinib verbetert sterk de overall overleving bij anaplastische schildklierkanker

28 november 2024: Bron: AMA Oncol. Published online October 24, 2024

Immuuntherapie met een combinatie van het anti-PD medicijn Atezolizumab (Tecentriq) gecombineerd met een gerichte behsndeling van vemurafenib (Zelboraf) plus cobimetinib (Cotellic) geeft een veel langere mediane algehele overleving (OS) en ziekteprogressievrije tijd bij patiënten met anaplastische schildklierkanker in vergelijking met standaard behandelingen zoals historisch onderzocht.

Dat blijkt uit een niet gerandomiseerde fase II studie bij drie groepen van patiënten met anaplastische schildklierkanker.

Patiënten die deelnamen aan het onderzoek werden verdeeld in 3 groepen:

groep 1 voor patiënten met gemuteerde BRAF V6OOE-tumoren die vemurafenib (Zelboraf) + cobimetinib (Cotellic) plus Atezolizumab (Tecentriq) kregen;
groep 2 voor patiënten met gemuteerde RAS- of NF1/2-tumoren die cobimetinib (Cotellic)plus Atezolizumab (Tecentriq) kregen;
groep 3 voor patiënten zonder een van deze varianten die bevacizumab (Avastin) plus Atezolizumab (Tecentriq) kregen.

Over alle 3 de groepen gemeten was de mediane overall overleving (OS) 18,23 maanden en de mediane follow-up tijd was 18,97 maanden.

Voor groep 1 (n = 19) was de mediane overall overleving (OS) en ziekte progressievrije overleving (PFS) 43,24 maanden (95% BI, 16 maanden niet schatbaar ) en 13,93 maanden.
Voor groep 2 (n = 21) waren deze 8,74 maanden en 4,80 maanden.
Voor groep 3 (n = 3) waren deze respectievelijk 6,21 maanden en 1,3 maanden.
De mediane follow-uptijd voor groepen 1 en 2 bedroeg respectievelijk 42,14 maanden (95% BI, 2,66-72,11) en 8,74 maanden (95% BI, 0,43-55,92).

"De combinatie van genetisch gematchte gerichte therapie plus immuuntherapie combinatie in de groepen 1 tot 3 resulteerden in een mediane overall overleving (OS) van 19 maanden - voor zover wij weten de langste OS die tot nu toe is gerapporteerd in een klinische studie bij patienten met anaplastisch schildklierkanker, waarmee het primaire doel van de studie werd bereikt", aldus de auteurs van de studie.

Vóór de behandeling werd een inductiefase van paclitaxel van 80 mg/m2 of nab-paclitaxel van 125 mg/m2 wekelijks toegediend, tot 3 doses, om de mutatiegedreven gerichte behandeling te vergemakkelijken.
Patiënten die voldoende resultaten hadden dankzij de behandeling, mochten bestraling bij hun operatie achterwege laten om hun locoregionale ziekte tijdens de studie onder controle te houden.

Bijwerkingen (AE's) werden opgemerkt in alle drie de groepen. Er was 1 sterfgeval mogelijk veroorzaakt door deelname aan de studie die te wijten was aan een darmperforatie in groep 1. Andere ernstige bijwerkingen (AE's) waren colitis, papiloedeem vanwege zenuwneuritis, retinopathie, linkerventrikeldisfunctie/verminderde ejectiefractie, pneumonitis, pancreatitis en slokdarmperforatie.

Het primaire einddoel was mediane overasll overleving (OS) en de secundaire doelen waren de algehele objectieve respons (ORR) en ziekte progressie vrije overleving (PFS). ORR voor de patiënten uit groep 1 was 50%, voor patiënten uit groep 2 was 14% en voor patiënten uit groep 3 was 33%.
Een complete remissie van 5,6% werd alleen opgemerkt in groep 1. In de groepen 1 tot en met 3 waren 20 patiënten 2 jaar in leven en moesten 15 patiënten met anaplastisch schildklierkanker langer dan 12 maanden worden behandeld.

Het uiteindelijke resultaat van de studie is dat van de 12 patiënten met locoregionale tumoren die tijdens de behandeling operabel werden, 11 patiënten ervoor kozen om een operatie te ondergaan en 8 van hen bij het opmaken van de resultaten nog in leven zijn. Van deze gevallen waren er 4 in stadium IVB en 8 in stadium IVC. Als gevolg van de operatie hadden 2 patiënten tijdelijke tracheostomieën en/of postoperatieve bestraling nodig.

Het volledige stuierapport is gratis in te zien. Klik op de titel van het abstract:

Key Points

Question What is the efficacy of combination targeted therapy plus checkpoint inhibition in patients with anaplastic thyroid cancer (ATC)?

Findings In this nonrandomized, phase 2 trial of 42 patients with ATC assigned to genetically-matched targeted therapy plus immune checkpoint inhibitors, there were 3 genetically-matched targeted therapy cohorts (BRAF V600E variant: vemurafenib/cobimetinib; RAS or NF variant: cobimetinib; non-BRAF/RAS/NF variant: bevacizumab). All patients received the immune checkpoint inhibitor, atezoliuzumab.

Meaning The trial met its primary end point, and demonstrated the longest overall survival published to date for systemic therapy in patients with ATC, and should be studied further.

Abstract

Importance Anaplastic thyroid carcinoma (ATC) is a rare and lethal cancer. Although progress has been made in recent years in patients with mutated BRAF tumors, those who respond initially eventually die of their disease; furthermore, there are no approved therapies for non-BRAF mutated tumors.

Objective To determine whether treatment with matched-targeted therapy plus immune checkpoint inhibitors were associated with improved overall survival (OS).

Design, Setting, and Participants A phase 2 trial at a single center, tertiary institution with parallel cohorts, assigning treatment with targeted therapy according to the tumor mutation status. Patients with mutated BRAF V600E tumors received vemurafenib/cobimetinib plus atezolizumab (cohort 1); those with mutated RAS (NRAS, KRAS, or HRAS) or NF1/2 tumors received cobimetinib plus atezolizumab (cohort 2). Patients without any of these variants were assigned to receive bevacizumab plus atezolizumab (cohort 3). Patients were enrolled from August 3, 2017, to July 7, 2021. All consecutive, systemic therapy-naive patients with ATC with active disease and who met eligibility criteria were considered for participation. The analysis was conducted in September 2023.

Interventions Patients were assigned to targeted therapy based on the driver mutation as follow: BRAF V600E (cohort 1, vemurafenib plus cobimetinib), RAS/NF (cohort 2, cobimetinib), or non-BRAF/RAS/NF (cohort 3, bevacizumab). All received atezolizumab.

Main Outcomes and Measures The primary outcome of the study was median OS of the entire targeted therapy cohort, compared with historical median OS of 5 months.

Results Forty-three patients with ATC were enrolled in the targeted therapy cohorts, of which 42 were included in the primary analysis. The median OS in patients across these 3 cohorts was 19 months (95% CI, 7.79-43.24). Median OS and progression-free survival per cohort were as follows: cohort 1: 43 months (95% CI, 16-not estimable ), 13.9 months (6.6-64.1); cohort 2: 8.7 months (95% CI, 5.1-37.0) and 4.8 months (1.8-14.7); cohort 3 (vascular endothelial growth factor inhibitor group): 6.21 months (4.1-NE) and 1.3 months (1.3-NE), respectively.

Conclusions and Relevance In this nonrandomized clinical trial, atezolizumab combined with targeted therapy resulted in a longer median OS than historical landmark, achieving the study’s primary end point, with cohort 1 achieving the longest OS.

Trial Registration ClinicalTrials.gov Identifier: NCT03181100

Article Information

Accepted for Publication: July 8, 2024.

Published Online: October 24, 2024. doi:10.1001/jamaoncol.2024.4729

Corresponding Author: Maria E. Cabanillas, MD, University of Texas MD Anderson Cancer Center, 1515 Holcombe, Unit 1461, Houston, TX 77030 (mcabani@mdanderson.org).

Author Contributions: Dr Cabanillas had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Dadu and Ferrarotto were co-second authors.

Concept and design: Cabanillas, Dadu, Ferrarotto, Fellman, Zafereo, Wang, Woodman, Busaidy.

Acquisition, analysis, or interpretation of data: Cabanillas, Ferrarotto, Gule-Monroe, Liu, Fellman, Williams, Zafereo, Wang, Lu, Ning, McKinley, Woodman, Duose, Gunn, Busaidy.

Drafting of the manuscript: Cabanillas, McKinley, Woodman, Busaidy.

Critical review of the manuscript for important intellectual content: Cabanillas, Dadu, Ferrarotto, Gule-Monroe, Liu, Fellman, Williams, Zafereo, Wang, Lu, Ning, Woodman, Duose, Gunn, Busaidy.

Statistical analysis: Cabanillas, Liu, Fellman, McKinley.

Obtained funding: Cabanillas.

Administrative, technical, or material support: Cabanillas, Ferrarotto, Wang, McKinley, Duose, Busaidy.

Supervision: Cabanillas, Dadu, Zafereo, Wang, Woodman, Gunn, Busaidy.

Conflict of Interest Disclosures: Dr Cabanillas reported grants from Genetech and Merck, and personal fees from Novartis during the conduct of the study; personal fees from Bayer and Exelixis outside the submitted work. Dr Dadu reported grants from Exelixis, Eisai, Merck, and AstraZeneca, personal fees from Bayer, Novartis, and Exelixis during the conduct of the study. Dr Ferrarotto reported personal advisory board fees from Prelude Therapeutics, Regeneron, Elevar Therapeutics, Coherus Bioscience, Eisai, and Remix therapeutics, personal fees from Sanofi/Aventis for educational talk, personal fees for answers in CME educational talk, and personal fees from Labcopr Drug Development DSMC outside the submitted work; and royalties from UpToDate (olfactory neuroblastoma chapter). Dr Gule-Monroe reported grants from Bayer pharmaceuticals for an educational grant and salary support from Siemens as part of an institutional development deal outside the submitted work. Dr Williams reported grants from Bayer and speakers fees from Springer Health outside the submitted work. Dr Zafereo reported grants from Merck for a phase 2 clinical trial (grant to institution), grants from Eli Lilly for a phase 2 clinical trial (grant to institution), personal fees from American Academy of Otolaryngology–Head & Neck Surgery, and personal fees from Thyroid International Recommedations Online outside the submitted work. Dr Duose reported grants from MDA during the conduct of the study. Dr Busaidy reported grants from GSK, personal fees from Eisai, and personal fees from Exelixis outside the submitted work. No other disclosures were reported.

Funding/Support: The study was supported by Genentech, the Rare Tumor Initiative as a part of the STrategic Research Initiative DEvelopment (STRIDE) program at The University of Texas MD Anderson Cancer Center and by the National Institutes of Health through MD Anderson’s Cancer Center Support (grant CA016672).

Role of the Funder/Sponsor: The sponsor played a role in the design and conduct of the study, as well as the approval of the manuscript and decision to submit the manuscript for publication.

Group Information: The members of The Rare Tumor Initiative Team are in Supplement 3.

Additional Contributions: We thank the patients who participated in this clinical trial, as well as their families and friends who supported them through this devastating disease. We also thank our research staff, nurses, and consultants who helped care for our patients. Last, we pay our gratitude and our respects to our colleague, Kenneth Hess, PhD, from the Department of Biostatistics who passed away before he could see the contributions of his work on this clinical trial.

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Immuuntherapie, Atezolizumab, gerichte behandeling, targeted therapy, vemurafenib + cobimetinib, bevacizumab, ziekte progressievrije tijd, overall overleving, anaplastische schildklierkanker, fase II studie, bevacizumab, BRAF V6OOE, RAS of NF1/2 tumoren