MO01.32 CodeBreaK 200: A Phase 3 Multicenter Study of Sotorasib, a KRAS(G12C) Inhibitor, versus Docetaxel in Patients with Previously Treated Advanced Non-Small Cell Lung Cancer (NSCLC) Harboring KRAS p.G12C Mutation

Reck, Martin; Spira, Alexander I.; Besse, Benjamin; Wolf, Juergen; Skoulidis, Ferdinandos; Borghaei, Hossein; Goto, Kōichi; Park, K.; Griesinger, Frank; Font, E. Felip; Boyer, Michael; Barrios, Carlos H.; Goss, Glenwood D.; Yang, Hui; Obiozor, Cynthia; Ramalingam, Suresh S.

doi:10.1016/j.jtho.2020.10.137

Cited by 9 publications

(6 citation statements)

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“…However, similar success was not seen in the CRC cohort (n = 62), in which the ORR was 9.7% 79 . Sotorasib is currently being compared with docetaxel in the second or later line treatment of advanced-stage KRAS G12C -mutant NSCLC (after progression on both an ICI and platinum-based doublet chemotherapy, individually or combined) in the phase III CodeBreaK 200 trial, with a primary end point of PFS 80 . Trials in the first-line setting are also ongoing (NCT04933695), and a multitude of trials are testing sotorasib alone or in combination with other agents across various settings in NSCLC and beyond (Table 1 and Supplementary Table 1).…”

Section: Kras G12c Inhibitors In the Clinicmentioning

confidence: 99%

The current state of the art and future trends in RAS-targeted cancer therapies

et al. 2022

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Section: Kras G12c Inhibitors In the Clinicmentioning

confidence: 99%

The current state of the art and future trends in RAS-targeted cancer therapies

et al. 2022

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“…As an example, PD-1/ PD-L1 inhibitors showed significant clinical benefit in patients with non-small cell lung cancer (NSCLC), but in several trials this was because they were evaluated compared to placebo [30][31][32]. Additionally, trials assessing promising agents as second-line treatment for patients with advanced NSCLC have used chemotherapy agents with modest clinical benefit, including docetaxel, in the comparator arm (NCT04427072) [33,34]. Lastly, due to the large variability in patients' baseline characteristics, comorbidities, and unique tumor molecular profiles and microenvironments, even carefully planned trials are not able to account for all the differences between the randomized arms, resulting in imbalances that may influence outcomes [35].…”

Section: Traditional Clinical Trial Designmentioning

confidence: 99%

Clinical trial design in the era of precision medicine

et al. 2022

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Recent rapid biotechnological breakthroughs have led to the identification of complex and unique molecular features that drive malignancies. Precision medicine has exploited next-generation sequencing and matched targeted therapy/immunotherapy deployment to successfully transform the outlook for several fatal cancers. Tumor and liquid biopsy genomic profiling and transcriptomic, immunomic, and proteomic interrogation can now all be leveraged to optimize therapy. Multiple new trial designs, including basket and umbrella trials, master platform trials, and N-of-1 patient-centric studies, are beginning to supplant standard phase I, II, and III protocols, allowing for accelerated drug evaluation and approval and molecular-based individualized treatment. Furthermore, real-world data, as well as exploitation of digital apps and structured observational registries, and the utilization of machine learning and/or artificial intelligence, may further accelerate knowledge acquisition. Overall, clinical trials have evolved, shifting from tumor type-centered to gene-directed and histology-agnostic trials, with innovative adaptive designs and personalized combination treatment strategies tailored to individual biomarker profiles. Some, but not all, novel trials now demonstrate that matched therapy correlates with superior outcomes compared to non-matched therapy across tumor types and in specific cancers. To further improve the precision medicine paradigm, the strategy of matching drugs to patients based on molecular features should be implemented earlier in the disease course, and cancers should have comprehensive multi-omic (genomics, transcriptomics, proteomics, immunomic) tumor profiling. To overcome cancer complexity, moving from drug-centric to patient-centric individualized combination therapy is critical. This review focuses on the design, advantages, limitations, and challenges of a spectrum of clinical trial designs in the era of precision oncology.

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“…TRAEs at this dose occurred in 20.6% and were similar to phase I results. CodeBreak 200, a phase III study investigating AMG 510 versus docetaxel in previouslytreated NSCLC has also begun recruiting with results awaited [95]. However, the success of the phase II portion of CodeBreak 100 led to FDA fast-track designation, a programme designed to expedite the development and regulatory review of potentially significant medicines [96].…”

Section: Clinical Data With Kras-g12c Inhibitorsmentioning

confidence: 99%

Drugging the Undruggable: Advances on RAS Targeting in Cancer

Molina‐Arcas

Samani

Downward

2021

Genes

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Around 20% of all malignancies harbour activating mutations in RAS isoforms. Despite this, there is a deficiency of RAS-targeting agents licensed for therapeutic use. The picomolar affinity of RAS for GTP, and the lack of suitable pockets for high-affinity small-molecule binding, precluded effective therapies despite decades of research. Recently, characterisation of the biochemical properties of KRAS-G12C along with discovery of its ‘switch-II pocket’ have allowed development of effective mutant-specific inhibitors. Currently seven KRAS-G12C inhibitors are in clinical trials and sotorasib has become the first one to be granted FDA approval. Here, we discuss historical efforts to target RAS directly and approaches to target RAS effector signalling, including combinations that overcome limitations of single-agent targeting. We also review pre-clinical and clinical evidence for the efficacy of KRAS-G12C inhibitor monotherapy followed by an illustration of combination therapies designed to overcome primary resistance and extend durability of response. Finally, we briefly discuss novel approaches to targeting non-G12C mutant isoforms.

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MO01.32 CodeBreaK 200: A Phase 3 Multicenter Study of Sotorasib, a KRAS(G12C) Inhibitor, versus Docetaxel in Patients with Previously Treated Advanced Non-Small Cell Lung Cancer (NSCLC) Harboring KRAS p.G12C Mutation

Cited by 9 publications

References 0 publications

The current state of the art and future trends in RAS-targeted cancer therapies

The current state of the art and future trends in RAS-targeted cancer therapies

Clinical trial design in the era of precision medicine

Drugging the Undruggable: Advances on RAS Targeting in Cancer

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