Sotorasib in KRASG12C mutated lung cancer: Can we rule out cracking KRAS led to worse overall survival?
The KRAS oncogene is present in up to 25% of solid tumors and for decades had been undruggable. Sotorasib was the first-in-class KRAS inhibitor to reach the US and European market, and its pharmacological inhibition is restricted to the KRAS p.G12C mutation. Sotorasib showed activity (tumor shrinkag...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-02-01
|
| Series: | Translational Oncology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523322002509 |
| _version_ | 1797956240604659712 |
|---|---|
| author | Timothée Olivier Alyson Haslam Vinay Prasad |
| author_facet | Timothée Olivier Alyson Haslam Vinay Prasad |
| author_sort | Timothée Olivier |
| collection | DOAJ |
| description | The KRAS oncogene is present in up to 25% of solid tumors and for decades had been undruggable. Sotorasib was the first-in-class KRAS inhibitor to reach the US and European market, and its pharmacological inhibition is restricted to the KRAS p.G12C mutation. Sotorasib showed activity (tumor shrinkage) in patients with non-small cell lung cancer harboring this specific mutation, and efficacy was tested in the CodeBreaK 200, open-label, phase 3 trial (NCT04303780). The results were presented in the ESMO 2022 meeting. CodeBreaK 200 found an improvement in the primary endpoint of progression-free survival (PFS), but overall survival, a key secondary endpoint, was not improved. However, critical questions about the trial's design may limit inferences regarding the reported results. The control arm treatment was inferior to the best standard of care. A late protocol modification (which lowered the sample size and allowed a problematic crossover) prohibited the trial from making a determination regarding overall survival. Imbalance in censoring rates, with potential informative censoring, makes PFS estimates unreliable. Quality-of-life data were also limited. Ultimately, CodeBreaK 200 does not clarify how this therapy should be used in practice, and while we maintain cautious enthusiasm for this and other Ras inhibitors, we await more informative trials |
| first_indexed | 2024-04-10T23:45:53Z |
| format | Article |
| id | doaj.art-696bc5e56a654a6ab608120ebd3f09e2 |
| institution | Directory Open Access Journal |
| issn | 1936-5233 |
| language | English |
| last_indexed | 2024-04-10T23:45:53Z |
| publishDate | 2023-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj.art-696bc5e56a654a6ab608120ebd3f09e22023-01-11T04:28:38ZengElsevierTranslational Oncology1936-52332023-02-0128101591Sotorasib in KRASG12C mutated lung cancer: Can we rule out cracking KRAS led to worse overall survival?Timothée Olivier0Alyson Haslam1Vinay Prasad2Department of Oncology, Geneva University Hospital, 4 Gabrielle-Perret-Gentil Street, 1205, Geneva, Switzerland; Department of Epidemiology and Biostatistics, University of California San Francisco, 550 16th St, 2nd Fl, San Francisco, CA 94158, USA; Corresponding author at: Department of Oncology, Geneva University Hospital, 4 Gabrielle-Perret-Gentil Street, Geneva, Switzerland.Department of Epidemiology and Biostatistics, University of California San Francisco, 550 16th St, 2nd Fl, San Francisco, CA 94158, USADepartment of Epidemiology and Biostatistics, University of California San Francisco, 550 16th St, 2nd Fl, San Francisco, CA 94158, USAThe KRAS oncogene is present in up to 25% of solid tumors and for decades had been undruggable. Sotorasib was the first-in-class KRAS inhibitor to reach the US and European market, and its pharmacological inhibition is restricted to the KRAS p.G12C mutation. Sotorasib showed activity (tumor shrinkage) in patients with non-small cell lung cancer harboring this specific mutation, and efficacy was tested in the CodeBreaK 200, open-label, phase 3 trial (NCT04303780). The results were presented in the ESMO 2022 meeting. CodeBreaK 200 found an improvement in the primary endpoint of progression-free survival (PFS), but overall survival, a key secondary endpoint, was not improved. However, critical questions about the trial's design may limit inferences regarding the reported results. The control arm treatment was inferior to the best standard of care. A late protocol modification (which lowered the sample size and allowed a problematic crossover) prohibited the trial from making a determination regarding overall survival. Imbalance in censoring rates, with potential informative censoring, makes PFS estimates unreliable. Quality-of-life data were also limited. Ultimately, CodeBreaK 200 does not clarify how this therapy should be used in practice, and while we maintain cautious enthusiasm for this and other Ras inhibitors, we await more informative trialshttp://www.sciencedirect.com/science/article/pii/S1936523322002509Non-small cell lung cancerKRAS inhibitorsBiomarkerInformative censoringPower analysis |
| spellingShingle | Timothée Olivier Alyson Haslam Vinay Prasad Sotorasib in KRASG12C mutated lung cancer: Can we rule out cracking KRAS led to worse overall survival? Translational Oncology Non-small cell lung cancer KRAS inhibitors Biomarker Informative censoring Power analysis |
| title | Sotorasib in KRASG12C mutated lung cancer: Can we rule out cracking KRAS led to worse overall survival? |
| title_full | Sotorasib in KRASG12C mutated lung cancer: Can we rule out cracking KRAS led to worse overall survival? |
| title_fullStr | Sotorasib in KRASG12C mutated lung cancer: Can we rule out cracking KRAS led to worse overall survival? |
| title_full_unstemmed | Sotorasib in KRASG12C mutated lung cancer: Can we rule out cracking KRAS led to worse overall survival? |
| title_short | Sotorasib in KRASG12C mutated lung cancer: Can we rule out cracking KRAS led to worse overall survival? |
| title_sort | sotorasib in krasg12c mutated lung cancer can we rule out cracking kras led to worse overall survival |
| topic | Non-small cell lung cancer KRAS inhibitors Biomarker Informative censoring Power analysis |
| url | http://www.sciencedirect.com/science/article/pii/S1936523322002509 |
| work_keys_str_mv | AT timotheeolivier sotorasibinkrasg12cmutatedlungcancercanweruleoutcrackingkrasledtoworseoverallsurvival AT alysonhaslam sotorasibinkrasg12cmutatedlungcancercanweruleoutcrackingkrasledtoworseoverallsurvival AT vinayprasad sotorasibinkrasg12cmutatedlungcancercanweruleoutcrackingkrasledtoworseoverallsurvival |