Molecularly matched therapy in the context of sensitivity, resistance, and safety; patient outcomes in end-stage cancer – the MetAction study

Abstract

Background: In precision cancer medicine, the challenge is to prioritize DNA driver events, account for resistance markers, and procure sufficient information for treatment that maintains patient safety. The MetAction project, exploring how tumor molecular vulnerabilities predict therapy response, first established the required workflow for DNA sequencing and data interpretation (2014)(2015). Here, we employed it to identify molecularly matched therapy and recorded outcome in end-stage cancer (2016)(2017)(2018)(2019). Material and methods: Metastatic tissue from 26 patients (16 colorectal cancer cases) was sequenced by the Oncomine assay. The study tumor boards interpreted called variants with respect to sensitivity or resistance to matched therapy and recommended single-agent or combination treatment if considered tolerable. The primary endpoint was the rate of progression-free survival 1.3-fold longer than for the most recent systemic therapy. The objective response rate and overall survival were secondary endpoints. Results: Both common and rare actionable alterations were identified. Thirteen patients were found eligible for therapy following review of tumor sensitivity and resistance variants and patient tolerability. The interventions were inhibitors of ALK/ROS1-, BRAF-, EGFR-, FGFR-, mTOR-, PARP-, or PD-1-mediated signaling for 2-3 cases each. Among 10 patients who received treatment until radiologic evaluation, 6 (46% of the eligible cases) met the primary endpoint. Four colorectal cancer patients (15% of the total study cohort) had objective response. The only serious adverse event was a transient colitis, which appeared in 1 of the 2 patients given PD-1 inhibitor with complete response. Apart from those two, overall survival was similar for patients who did and did not receive study treatment. Conclusions: The systematic MetAction approach may point forward to a refined framework for how to interpret the complexity of sensitivity versus resistance and patient safety that resides in tumor sequence data, for the possibly improved outcome of precision cancer medicine in future studies. ClinicalTrials.gov, identifier: NCT02142036ARTICLE HISTORY

Improving public cancer care by implementing precision medicine in Norway: IMPRESS-Norway

“…Less than 7% of cancer patients were estimated to benefit from genome-guided anti-cancer therapies in the US in 2018 [ 9 ]. Other studies using genomic profiling approaches with individualized matching of molecular variant and drug, report low inclusion rate and modest overall rate of clinical benefit [ 10 ], although much higher than the first generation precision medicine trials in oncology [ 11 – 13 ]. This is probably due to increasing knowledge about actionable genes and driver mutations in tumour development, resistance mechanisms, a more refined diagnostic work-up and availability of new targeted therapeutics [ 14 ].…”

ALK Inhibitors in Patients With ALK Fusion–Positive GI Cancers: An International Data Set and a Molecular Case Series

“…We assembled an international data set of 13 published 5,[12][13][14][15] (n = 6) and nonpublished (n = 7) cases of ALK fusionpositive GI cancer patients treated with ALKi. We collected information about social and demographic characteristics of patients, primary tumor site and histology, ALK fusion partner or site of breakpoint, microsatellite status, or other baseline next-generation sequencing (NGS)/mutational data.…”

Presisjonsmedisin ved kreft – førebels føremålstenleg for dei få

“…Det viktigaste viste seg å vere kompetansebygging blant alle involverte fagpersonar. I neste del av studien, med inklusjon av 26 pasientar frå mars 2016 til mars 2017, fekk ti av dei behandling basert på NGS-data frå metastatisk svulstvev (3). Av desse oppnådde to tarmkreftpasientar partiell behandlingsrespons som varte 10-17 veker før ny sjukdomsprogresjon.…”

“…Hos tre studiepasientar med gastrointestinal kreft identifiserte vi ALK-eller ROS1-fusjon som antatt drivarmutasjon, kor crizotinib gjev overtydande behandlingseffektar ved avansert ikkje-småcella lungekreft (5,18). Men MetAction-pasientane hadde ingen effekt av crizotinib, noko som er ein brest for konseptet om biologisk målretta medikament utanfor etablert indikasjon (3). Konklusjon I MetAction-studien tok vi omsyn til svulstmutasjonar som tilsa resistens så vel som respons på terapi.…”

“…No i 2020 viser akkumulerte data frå naer 20 000 pasientar at 5 % eller enda faerre har hatt sikker effekt av slik behandling gjeven utanfor etablert indikasjon (2,3). Som onkologar pliktar vi å gje nøktern informasjon til våre pasientar med avansert kreftsjukdom, så vel som i den helsepolitiske debatten, om eventuell nytte av presisjonskreftmedisin.…”