Under a Cancer Cell Spotlight: unleashing the promise of KRAS targeting therapy

Published today in Cancer Cell* as a Spotlight piece, co-authors Josep Tabernero, VHIO’s Director, and Elena Élez, Clinical Investigator of our Gastrointestinal and Endocrine Tumors Group, elegantly review the findings from the phase I, multicenter open-label CodeBreak 100 trial of sotorasib in patients with advanced solid tumors harboring the KRASG12C mutation (Hong el al. 2020).

The authors begin by updating on the specificities of RAS family mutations, with KRAS oncoproteins under their lens as they go on to provide a superb summary followed by insightful observations regarding the promise and limitations of the results from CodeBreak 100 study that were recently published in The New England Journal of Medicine**.

“Twenty per cent of all cancers harbor RAS mutations totalling at an estimated 3.4 million new cases each year globally. We must therefore strive to more effectively target the RAS family of proteins with KRAS particularly under our investigative fire as the most frequently mutated across several tumor types,” observed co-author Josep Tabernero, who is also Head of the Medical Oncology Department at the Vall d’Hebron University Hospital (HUVH – Vall d’Hebron Barcelona Hospital Campus).

Representing an important development in the collective ambition of more effectively targeting KRAS mutations in cancer, this study evaluated the efficacy of inhibiting KRASG12C -a mutation occurring in 13% of non-small-cell lung cancers (NSCLCs) and in 1-3% of colorectal cancers (CRCs) as well as others – with sotorasib in 129 heavily pretreated patients with advanced solid tumors. Specifically, 59 patients with NSCLC, 42 with colorectal cancer, and 28 with other tumors, who had received a median of 3 previous lines of anticancer therapies for metastatic disease, were included in dose escalation and expansion cohorts.

In their review of the results, the Spotlight co-authors shine light on the fact that the CRC cohort showed a poorer response rate to treatment with sotorasib compared to that observed in NSCLC. In the NSCLC subgroup 32.2% (19 patients) had a confirmed objective response, and in patients with CRC objective response was 7.1%, with disease control at 88.1% (52 patients) and 73.8% (31 patients), respectively. Interestingly, they note that this lower rate in CRC trends in other studies targeting RAS mutant cancers. Josep and Elena highlight various examples and go on to draw on other findings (Amodio V et al. 2020) showing that the combination of KRASG12C and EGFR blockade can effectively overcome this mutation’s adaptive response to inhibition as observed in cell lines and patient-derived models.

They also briefly discuss the results of from the KRYSTAL-1 study (Johnson ML et al. 2020) which explored novel approaches to surpress gene expression and harness the immune system to more effectively thwart disease. The investigators combined KRASG12C inhibitor adagrasib with immunotherapy pembrolizumab, or pembrolizumab and afatinib in NSCLC, and cetuximab and adagrasib in CRC patients. Based on results thus far, the investigators will now seek to assess the efficacy of combining cetuximab plus adagrasib in this patient population.

Commenting for VHIO’s Global Communications Elena Élez, also a Medical Oncologist at HUVH’s Medical Oncology Department, noted “In our collective efforts to develop anti-cancer therapies that more effectively target KRAS, results from CodeBreak 100 provide important insights toward developing more potent and precise treatment strategies against CRC. They also underpin the necessity of factoring in the underlying biology of each tumor type.”

“This study represents important progress in drugging the undruggable. Findings support that the best treatment strategies and combinations must be based on both the histological and molecular features of each cancer, and that pharmacodynamic assessment and biomarker analysis in early phase, dynamic studies must be included to ultimately improve outcomes for our patients,” concluded Josep.



*Elena Elez, Josep Tabernero. The Effective Targeting of KRASG12C elusiveness. Spotlight. Cancer Cell 2020 Dec 14; 38(06):785-787. DOI: https:/doi.org/10.1016/j.ccell.2020.11.012.

**Hong D, Fakih M, Strickler J, Desai J, Durm G, Shapiro G, Falchook G, Price T, Sacher A, Delinger C et al. KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors. N Engl J Med 2020 Sep 24;383(13):1207-1217.