Outcomes of combination platinum-doublet chemotherapy and anti-PD(L)-1 blockade in KRAS(G12C) mutant non-small cell lung cancer Journal Article
| Authors: | Elkrief, A.; Riccuiti, B.; Alessi, J. V.; Fei, T.; Kalvin, H. L.; Egger, J. V.; Rizvi, H.; Thummalapalli, R.; Lamberti, G.; Plodkowski, A.; Hellmann, M. D.; Kris, M. G.; Arcila, M. E.; Baine, M. K.; Rudin, C. M.; Lito, P.; Ladanyi, M.; Schoenfeld, A. J.; Riely, G. J.; Awad, M. M.; Arbour, K. C. |
| Article Title: | Outcomes of combination platinum-doublet chemotherapy and anti-PD(L)-1 blockade in KRAS(G12C) mutant non-small cell lung cancer |
| Abstract: | Background: Direct KRASG12C inhibitors are approved for patients with non-small cell lung cancers (NSCLC) in the second-line setting. The standard-of-care for initial treatment remains immune checkpoint inhibitors, commonly in combination with platinum-doublet chemotherapy (chemo-immunotherapy). Outcomes to chemo-immunotherapy in this subgroup have not been well described. Our goal was to define the clinical outcomes to chemo-immunotherapy in patients with NSCLC with KRASG12C mutations. Patients and Methods: Through next-generation sequencing, we identified patients with advanced NSCLC with KRAS mutations treated with chemo-immunotherapy at 2 institutions. The primary objective was to determine outcomes and determinants of response to first-line chemo-immunotherapy among patients with KRASG12C by evaluating objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). We assessed the impact of coalterations in STK11/KEAP1 on outcomes. As an exploratory objective, we compared the outcomes to chemo-immunotherapy in KRASG12C versus non-G12C groups. Results: One hundred and thirty eight patients with KRASG12C treated with first-line chemo-immunotherapy were included. ORR was 41% (95% confidence interval (CI), 32-41), median PFS was 6.8 months (95%CI, 5.5-10), and median OS was 15 months (95%CI, 11-28). In a multivariable model for PFS, older age (P = .042), squamous cell histology (P = .008), poor ECOG performance status (PS) (P < .001), and comutations in KEAP1 and STK11 (KEAP1MUT/STK11MUT) (P = .015) were associated with worse PFS. In a multivariable model for OS, poor ECOG PS (P = .004) and KEAP1MUT/STK11MUT (P = .009) were associated with worse OS. Patients with KRASG12C (N = 138) experienced similar outcomes to chemo-immunotherapy compared to patients with non-KRASG12C (N = 185) for both PFS (P = .2) and OS (P = .053). Conclusions: We define the outcomes to first-line chemo-immunotherapy in patients with KRASG12C, which provides a real-world benchmark for clinical trial design involving patients with KRASG12C mutations. Outcomes are poor in patients with specific molecular coalterations, highlighting the need to develop more effective frontline therapies. © The Author(s) 2023. Published by Oxford University Press. |
| Keywords: | chemotherapy; carcinoma, non-small-cell lung; lung neoplasms; protein serine threonine kinase; lung tumor; immunotherapy; platinum; combination therapy; non-small cell lung cancer; non small cell lung cancer; transcription factor nrf2; kelch like ech associated protein 1; humans; human; nf-e2-related factor 2; protein serine-threonine kinases; kelch-like ech-associated protein 1; kras<sup>g12c</sup> |
| Journal Title: | The Oncologist |
| Volume: | 28 |
| Issue: | 11 |
| ISSN: | 1083-7159 |
| Publisher: | Oxford University Press |
| Date Published: | 2023-11-01 |
| Start Page: | 978 |
| End Page: | 985 |
| Language: | English |
| DOI: | 10.1093/oncolo/oyad197 |
| PUBMED: | 37589215 |
| PROVIDER: | scopus |
| PMCID: | PMC10628591 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is Kathryn C. Arbour -- Source: Scopus |
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