Comparative effectiveness analysis between entrectinib clinical trial and crizotinib real-world data in<i>ROS1</i>+ NSCLC

Pérez, Laura Mezquita; Trinh, Huong; Martinec, Michael; Martina, Reynaldo; Riehl, Todd; Krebs, Matthew; Wong, William; Crane, Gracy

doi:10.2217/cer-2021-0131

Cited by 16 publications

(9 citation statements)

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“…The use of real-world control arms is emerging in oncology as an approach to evaluate rare and challenging cohorts such as clinical outcomes for rare biomarker-positive populations with the Flatiron Health database [ 32 , 33 ]. To our knowledge the only other study using real-world data to estimate the comparative effectiveness of CGP to inform treatment in advanced pan-cancer is a recent article by Weymann et al [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Comparing Survival Outcomes for Advanced Cancer Patients Who Received Complex Genomic Profiling Using a Synthetic Control Arm

et al. 2022

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Background Complex genomic profiling (CGP) has transformed cancer treatment decision making, yet there is a lack of robust and quantifiable evidence for how utilisation of CGP improves patient outcomes. Objective This study evaluated cohort level clinical effectiveness of CGP to improve overall survival (OS) in real-world advanced cancer patients using a registry-based matched control population. Patients and methods Two cohorts of advanced and refractory cancer patients were seen in consecutive series for early phase trial enrolment consideration. The first cohort (CGP group) accessed tumour profiling via a research study; while the second cohort that followed was not profiled. Overall survival between cohorts was compared using Kaplan-Meier curves and Cox proportional hazard models. Potential confounding was analysed and adjusted for using stabilised weights based on propensity scores. Results Within the CGP group, 25 (17.6%) patients received treatment informed by CGP results and this subgroup had significantly improved survival compared with CGP patients in whom results did not impact their treatment (unadjusted HR = 0.44, (0.22–0.88), p = 0.02). However, when comparing the entire CGP cohort with the No CGP cohort, no significant survival benefit was evident with adjusted median OS for CGP of 13.5 months (9.2–17.0) compared with 11.0 (9.2–17.4) for No CGP (adjusted HR = 0.92, (0.65–1.30), p = 0.63). Conclusions This study utilised real-world data to simulate a control arm and quantify the clinical effectiveness of genomic testing. The magnitude of survival benefit for patients who had CGP result-led treatments was insufficient to drive an overall survival gain for the entire tested population. Translation of CGP into clinics requires strategies to ensure higher rates of tested patients obtain clinical benefit to deliver on the value proposition of CGP in an advanced cancer population. Supplementary Information The online version contains supplementary material available at 10.1007/s11523-022-00910-0.

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Section: Discussionmentioning

confidence: 99%

Comparing Survival Outcomes for Advanced Cancer Patients Who Received Complex Genomic Profiling Using a Synthetic Control Arm

et al. 2022

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“…We compared two cohorts of patients with ROS1+ NSCLC. The entrectinib cohort included adults who received entrectinib from three open-label, single-cohort, Phase I/II trials: ALKA-372-001 (EudraCT2012-00148-88; n = 9), STARTRK-1 (NCT02097810; n = 7) and STARTRK-2 (NCT02568267; n = 78) [8,12,13]. All studies reported in this secondary analysis were funded by F Hoffmann-La Roche Ltd and were conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines and all patients provided written informed consent.…”

Section: Study Design and Populationmentioning

confidence: 99%

“…Entrectinib (ROZLYTREK™) is an oral tyrosine kinase inhibitor of ROS1, TRK, and ALK, that has demonstrated activity across various tumor types and histologies, including ROS1 fusion-positive (ROS1+) NSCLC [8,9,10]. Entrectinib received US FDA approval in August 2019 for the treatment of patients with ROS1+ NSCLC.…”

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Potential policy reforms to strengthen the accelerated approval pathway

2021

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The accelerated approval pathway for new drugs in the United States is often praised but faces growing criticism of whether it is finding the appropriate balance between uncertainty, access and cost. To support efforts to strengthen the pathway, this paper provides an analysis of key concerns and the advantages and disadvantages of ten potential policy reforms – those achievable through the US FDA action alone, and those that would require a combination of government, payer and life science industry actions. Accelerated approval sits at the heart of many of the controversies regarding drug approvals and pricing, and this analysis provides perspectives on how best to strengthen the pathway within the broader landscape of an innovative US healthcare system.

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“…6,8 Since its 2019 approval, pan-TRK/ROS1/ALK TKI entrectinib has been utilized for ROS1+ NSCLC due to its greater ability to cross the blood-brain barrier and therefore treat or delay brain metastases associated with ROS1+ NSCLC. [9][10][11] However, while entrectinib and crizotinib have significantly improved outcomes for patients, drug resistance to TKIs inevitably develops, leading to disease progression. Approximately one-third of ROS1+ NSCLC patients resistant to entrectinib demonstrate on-target ROS1 kinase domain (KD) mutations.…”

Section: Introductionmentioning

confidence: 99%

MET gene amplification is a mechanism of resistance to entrectinib in ROS1+ NSCLC

Tyler

Chen

et al. 2022

Thoracic Cancer

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Background: ROS1 tyrosine kinase inhibitors (TKIs) have demonstrated significant clinical benefit for ROS1+ NSCLC patients. However, TKI resistance inevitably develops through ROS1 kinase domain (KD) modification or another kinase driving bypass signaling. While multiple TKIs have been designed to target ROS1 KD mutations, less is known about bypass signaling in TKI-resistant ROS1+ lung cancers. Methods: Utilizing a primary, patient-derived TPM3-ROS1 cell line (CUTO28), we derived an entrectinib-resistant line (CUTO28-ER). We evaluated proliferation and signaling responses to TKIs, and utilized RNA sequencing, whole exome sequencing, and fluorescence in situ hybridization to detect transcriptional, mutational, and copy number alterations, respectively. We substantiated in vitro findings using a CD74-ROS1 NSCLC patient's tumor samples. Last, we analyzed circulating tumor DNA (ctDNA) from ROS1+ NSCLC patients in the STARTRK-2 entrectinib trial to determine the prevalence of MET amplification. Results: CUTO28-ER cells did not exhibit ROS1 KD mutations. MET TKIs inhibited proliferation and downstream signaling and MET transcription was elevated in CUTO28-ER cells. CUTO28-ER cells displayed extrachromosomal (ecDNA) MET amplification without MET activating mutations, exon 14 skipping, or fusions. The CD74-ROS1 patient samples illustrated MET amplification while receiving ROS1 TKI. Finally, two of 105 (1.9%) entrectinib-resistant ROS1+ NSCLC STARTRK-2 patients with ctDNA analysis at enrollment and disease progression displayed MET amplification. Conclusions: Treatment with ROS1-selective inhibitors may lead to MET-mediated resistance. The discovery of ecDNA MET amplification is noteworthy, as ecDNA is associated with more aggressive cancers. Following progression on ROS1-selective inhibitors, MET gene testing and treatments targeting MET should be explored to overcome MET-driven resistance.

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Comparative effectiveness analysis between entrectinib clinical trial and crizotinib real-world data inROS1+ NSCLC

Cited by 16 publications

References 30 publications

Comparing Survival Outcomes for Advanced Cancer Patients Who Received Complex Genomic Profiling Using a Synthetic Control Arm

Comparing Survival Outcomes for Advanced Cancer Patients Who Received Complex Genomic Profiling Using a Synthetic Control Arm

Potential policy reforms to strengthen the accelerated approval pathway

MET gene amplification is a mechanism of resistance to entrectinib in ROS1+ NSCLC

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