94% of researchers rate our articles as excellent or good
Learn more about the work of our research integrity team to safeguard the quality of each article we publish.
Find out more
Anneloes L. Noordhof1
Torsten Gerriet Blum2,3
Georgia Hardavella4
Lizza E. L. Hendriks5
Wouter H. van Geffen1*- 1Department of Respiratory Medicine, Medical Center Leeuwarden, Leeuwarden, Netherlands
- 2Department of Pneumology, Lungenklinik Heckeshorn, Helios Klinikum Emil von Behring, Berlin, Germany
- 3Department of Internal Medicine/Pneumonology, Medical School Berlin, Berlin, Germany
- 46th Department of Respiratory Medicine, “Sotiria” Athens’ Chest Diseases Hospital, Athens, Greece
- 5Department of Respiratory Medicine, GROW-Research Institute for Oncology and Reproduction, Maastricht University Medical Center, Maastricht, Netherlands
Editorial on the Research Topic
KRAS in stage IV non-small cell lung cancer
Despite the continuous development of drugs targeting actionable genomic alterations (AGA’s), lung cancer remains the leading cause of cancer related death worldwide (1–3). In European populations, the most common AGA in stage IV non-small cell lung cancer (NSCLC), adenocarcinoma type, is the Kirsten Rat Sarcoma virus oncogene (KRAS) mutation (4, 5). KRAS was long thought to be “undruggable”, but for one of the KRAS subtypes, the G12C mutation, targeted therapy has become available which has significantly changed the therapeutic landscape for KRAS G12C mutated NSCLC. However, immunotherapy with immune checkpoint inhibitors (ICI), either alone or in combination with chemotherapy, is still the current first line of treatment for all KRAS subtypes including G12C (6, 7).
In the second line and beyond, G12C inhibitors such as sotorasib and adagrasib have been approved for patients with KRAS G12C mutated NSCLC. These are small molecules that bind into a specific groove in the G12C molecule to prevent downstream signalling and cell survival. Sotorasib and adagrasib both showed overall response rates of around 40% in the CodeBreaK 100 and KRYSTAL-1 phase II studies respectively (8, 9).
In the phase III CodeBreaK 200 trial, where sotorasib was compared to docetaxel, patients receiving sotorasib had a significant longer median progression free survival (PFS) compared to those treated with docetaxel (5.6 months vs. 4.5 months). However, overall survival (OS) was not different among treatment groups (10). In the KRYSTAL-12 phase III trial comparing adagrasib to docetaxel, adagrasib also showed a significantly improved median PFS (5.5 months for adagrasib vs. 3.8 months for docetaxel), but OS data has not been reported yet (11). In both phase III-trials, all patients were previously treated with platinum-based chemotherapy and ICI.
Nevertheless, despite these recent developments, optimizing the treatment strategy of KRAS mutated NSCLC remains subject of interest as the outcomes with sotorasib and adagrasib are still below those achieved with targeted therapies for several other AGA’s. The combined research efforts in this Research Topic in Frontiers of Oncology “KRAS in stage IV non-small cell lung cancer” cover multiple aspects of important challenges in treating KRAS mutated NSCLC.
The prognostic role of KRAS has been a subject of debate both in the past when only chemotherapy was available, and also in the current immunotherapy era (12, 13). Peng et al. explored the survival of 112 patients with KRAS mutated NSCLC in a Chinese study. Although there were no differences in PFS, patients treated with an ICI-based regiment (± chemotherapy) had a significantly better OS than those treated with chemotherapy alone. This effect was also reported in separate KRAS G12C and non-G12C cohorts as well as in a subgroup harbouring a KRAS/TP53 co-mutation. This Chinese single centre study may have some limitations since it did not provide any information on the PD-L1 status, yet it offered an interesting insight into the survival of patients with a KRAS mutation in a non-Western cohort.
Notario et al. also aims to describe the clinical outcomes of 103 patients harbouring a KRAS mutation treated with ICI, mostly in first or second line, either as monotherapy or in combination with chemotherapy in a Spanish monocentric cohort. In this study, PD-L1 expression was higher among patients with the G12C subtype. Better OS and PFS were observed in patients with high PD-L1 expressing tumours, regardless of KRAS subtype mutation.
Although the focus in this Research Topic is on patients with stage IV disease, Eklund et al. published work from a different perspective. They describe the impact of the KRAS mutational status in patients with stage I-II NSCLC treated in a Swedish centre. The vast majority of these patients received surgical resection of their tumour. Of interest, although KRAS mutational status did not have a significant impact on OS, the authors reported a shorter OS in patients with a KRAS mutation: the mean (median not reached) OS was 63 months for patients with a KRAS mutation versus 74 months for patients without. The G12C mutation patients had a similar prognosis compared to those with non-G12C KRAS mutations. Since there were only 113 patients with a KRAS mutation in this study, larger studies are needed to establish the prognostic role of KRAS in this patient category.
KRAS is a heterogeneous disease, where multiple co-mutations can co-occur and may affect clinical outcomes. On this ground, Frille et al. advocate for extensive predictive testing including broad panels for mutation analysis to better estimate the prognosis and treatment options for patients with advanced NSCLC. They present the survival of more than 4000 patients with different mutations: KRAS, STK11, KEAP1 and TP53, either alone or in complex combinations. Patients with a KRAS-only mutation, or with a combination of KRAS + STK11 had the longest OS. The TP53-comutation showed a negative influence on KRAS mutated NSCLC, as in this group the OS was significantly reduced by more than 30%.
The narrative review of Sreter et al. offers a detailed overview regarding the molecular basis, the role of co-mutations and an overview of clinical evidence for KRAS inhibition with sotorasib and adagrasib. Moreover, they offer a review of literature of intracranial responses with these two G12C-inhibitors, and they propose mechanisms of acquired resistance to G12C-inhibitors and future strategies to overcome them.
Chour et el. provide a review in which they summarize the KRAS pathway and the mechanism of sotorasib and adagrasib, that both bind to the inactive GDP-bound state of KRAS. The also discuss mechanism of resistance to these G12C-inhibitors, either primary resistance, i.e. new co-occurring mutations that prevent the binding of inhibitors, or acquired resistance, for example gain-of-function mutations in other oncogenes and thereby bypassing KRAS.
Current guidelines advise testing for PD-L1 status and molecular testing for AGA in patients with metastatic NSCLC (6). However, obtaining histology or cytology samples can be challenging. Cai et al. preformed a systematic review and meta-analysis to investigate the diagnostic accuracy of KRAS detection in plasma samples. Plasma NGS could be a suitable alternative when tissue samples are not available as it detects KRAS with high accuracy.
Since G12C inhibitors are now available in the second line treatment setting and beyond, managing toxicity and optimal dosing of sotorasib remains a challenge. Shigaki et al. explored the possible relation between blood sotorasib levels and therapeutic outcomes and adverse event in five patients treated with sotorasib but found no association. Nevertheless, this is an interesting concept for further evaluation in a larger number of patients and it could possibly offer insights into more personalized dosing strategies in the future.
The combined efforts of these studies published in this Research Topic have contributed in decreasing the knowledge gap on how to optimize treatment strategies for patients with KRAS mutated NSCLC. The treatment landscape is anticipated to change further with the development of inhibitors of other KRAS mutational subtypes and pan-KRAS inhibitors (14). Ongoing research in the acquired resistance to G12-inhibitors and their administration in combination with other types of therapy could further change the treatment landscape, but additional research is needed in these areas.
Author contributions
AN: Conceptualization, Investigation, Methodology, Writing – original draft, Writing – review & editing. TB: Methodology, Supervision, Writing – review & editing. GH: Methodology, Supervision, Writing – review & editing. LH: Methodology, Supervision, Writing – review & editing. WvG: Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Validation, Writing – review & editing.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. (2021) 71:209–49. doi: 10.3322/caac.21660
2. Asmara OD, Tenda ED, Singh G, Pitoyo CW, Rumende CM, Rajabto W, et al. Lung cancer in Indonesia. J Thorac Oncol. (2023) 18:1134–45. doi: 10.1016/j.jtho.2023.06.010
3. Hendriks LEL, Dingemans AC, De Ruysscher DKM, Aarts MJ, Barberio L, Cornelissen R, et al. Lung cancer in the Netherlands. J Thorac Oncol. (2021) 16:355–65. doi: 10.1016/j.jtho.2020.10.012
4. Prior IA, Hood FE, Hartley JL. The frequency of ras mutations in cancer. Cancer Res. (2020) 80:2969–74. doi: 10.1158/0008-5472.CAN-19-3682
5. Moore AR, Rosenberg SC, McCormick F, Malek S. RAS-targeted therapies: is the undruggable drugged? Nat Rev Drug Discovery. (2020) 19:533–52. doi: 10.1038/s41573-020-0068-6
6. Hendriks LE, Kerr KM, Menis J, Mok TS, Nestle U, Passaro A, et al. Non-oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. (2023) 34:358–76. doi: 10.1016/j.annonc.2022.12.013
7. Noordhof AL, Swart EM, Damhuis RAM, Hendriks LEL, Kunst PWA, Aarts MJ, et al. Prognostic implication of KRAS G12C mutation in a real-world KRAS-mutated stage IV NSCLC cohort treated with immunotherapy in the Netherlands. JTO Clin Res Rep. (2023) 4:100543. doi: 10.1016/j.jtocrr.2023.100543
8. Skoulidis F, Li BT, Dy GK, Price TJ, Falchook GS, Wolf J, et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med. (2021) 384:2371–81. doi: 10.1056/NEJMoa2103695
9. Jänne PA, Riely GJ, Gadgeel SM, Heist RS, Ou SI, Pacheco JM, et al. Adagrasib in non-small-cell lung cancer harboring a KRASG12C mutation. N Engl J Med. (2022) 387:120–31. doi: 10.1056/NEJMoa2204619
10. De Langen AJ, Johnson ML, Mazieres J, Dingemans AC, Mountzios G, Pless M, et al. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRASG12C mutation: a randomised, open-label, phase 3 trial. Lancet. (2023) 401:733–46. doi: 10.1016/S0140-6736(23)00221-0
11. Mok TSK, Yao W, Duruisseaux M, Doucet L, Martínez AA, Gregorc V, et al. KRYSTAL-12: Phase 3 study of adagrasib versus docetaxel in patients with previously treated advanced/metastatic non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation [abstract. J Clin Oncol. (2024) 42:LBA8509–LBA8509. doi: 10.1200/JCO.2024.42.17_suppl.LBA8509
12. Mellema WW, Dingemans AM, Thunnissen E, Snijders PJ, Derks J, Heideman DA, et al. KRAS mutations in advanced nonsquamous non-small-cell lung cancer patients treated with first-line platinum-based chemotherapy have no predictive value. J Thorac Oncol. (2013) 8:1190–5. doi: 10.1097/JTO.0b013e318298764e
13. Noordhof AL, Damhuis RAM, Hendriks LEL, de Langen AJ, Timens W, Venmans BJW, et al. Prognostic impact of KRAS mutation status for patients with stage IV adenocarcinoma of the lung treated with first-line pembrolizumab monotherapy. Lung Cancer. (2021) 155:163–9. doi: 10.1016/j.lungcan.2021.04.001
Keywords: non-small cell lung cancer, lung adenocarcinoma, Kirsten Rat Sarcoma (KRAS), KRAS G12C, KRAS inhibitors
Citation: Noordhof AL, Blum TG, Hardavella G, Hendriks LEL and van Geffen WH (2025) Editorial: KRAS in stage IV non-small cell lung cancer. Front. Oncol. 14:1517049. doi: 10.3389/fonc.2024.1517049
Received: 25 October 2024; Accepted: 29 October 2024;
Published: 10 March 2025.
Edited and Reviewed by:
Alfredo Addeo, Hôpitaux Universitaires de Genève (HUG), SwitzerlandCopyright © 2025 Noordhof, Blum, Hardavella, Hendriks and van Geffen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Wouter H. van Geffen, d291dGVyLnZhbi5nZWZmZW5AbWNsLm5s