Skip to main content

Advertisement

SpringerLink
Log in

Anti-PD-(L)1 for KRAS-mutant advanced non-small–cell lung cancers: a meta-analysis of randomized–controlled trials

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Purpose

The most frequent mutation in advanced non-small–cell lung cancer (NSCLC), Kirsten rat-sarcoma viral oncogene (KRAS) is found in 20–25% of these patients’ tumors. While phase III trials on therapies targeting KRAS, especially KRASG12C, are ongoing, the clinical efficacy of anti-programmed death protein-1 (PD-1) or its ligand (PD-L1) against KRAS-mutant NSCLCs remains a topic of debate.

Methods

This meta-analysis examined randomized-trial data comparing first- or second-line anti-PD-(L)1 with or without chemotherapy vs. chemotherapy alone for advanced KRAS-mutant NSCLCs. Outcome measures included overall survival (OS) and progression-free survival (PFS). Analyses were computed using the Cochrane method of collaboration for meta-analyses, with Review Manager software (RevMan version 5.3; Oxford, UK).

Results

We analyzed 3 first-line trials (IMpower-150, Keynote-189 and Keynote-042) and 3 second-line trials (Oak, Poplar and CheckMate-057) that included 1313 NSCLCs (386 KRAS-mutant and 927 KRAS wild-type tumors). For KRAS-mutant NSCLCs, anti-PD-(L)1 with or without chemotherapy was significantly associated (hazard ratio [95% confidence interval]) with prolonged OS (0.59 [0.49–0.72]; p < 0.00001) and PFS (0.58 [0.43–0.78]; p = 0.0003) compared to chemotherapy alone. OS benefited in both first- and second-line trials. OS for patients with KRAS-mutant NSCLCs was significantly longer than that for those with KRAS wild-type tumors (p = 0.001).

Conclusions

Anti-PD-(L)1 with or without chemotherapy seemed to achieve longer OS and PFS than chemotherapy alone for patients with KRAS-mutant and wild-type KRAS advanced NSCLCs, with an even greater OS benefit for the former.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Planchard D, Popat S, Kerr K, Novello S, Smit EF, Faivre-Finn C et al (2018) Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol Off J Eur Soc Med Oncol. 29(Suppl 4):192–237

    Article  Google Scholar 

  2. El Osta B, Behera M, Kim S, Berry LD, Sica G, Pillai RN et al (2019) Characteristics and outcomes of patients with metastatic kras-mutant lung adenocarcinomas: the lung cancer mutation consortium experience. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer 14(5):876–889

    Google Scholar 

  3. Jordan EJ, Kim HR, Arcila ME, Barron D, Chakravarty D, Gao J et al (2017) Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discov juin 7(6):596–609

    Article  CAS  Google Scholar 

  4. Dogan S, Shen R, Ang DC, Johnson ML, D’Angelo SP, Paik PK et al (2012) Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers. Clin Cancer Res Off J Am Assoc Cancer Res 18(22):6169–6177

    Article  CAS  Google Scholar 

  5. Goulding RE, Chenoweth M, Carter GC, Boye ME, Sheffield KM, John WJ et al (2020) KRAS mutation as a prognostic factor and predictive factor in advanced/metastatic non-small cell lung cancer: a systematic literature review and meta-analysis. Cancer Treat Res Commun 24:100200

    Article  Google Scholar 

  6. Agyeman A, Vallejo JJ, Myers A, Blumenthal GM. (2018). Meta-analysis exploring the effect of oncogenic driver mutations on outcome of metastatic non-small cell lung cancer (mNSCLC) patients (pts) treated with immune checkpoint inhibitors (ICI) or docetaxel (doc). J Clin Oncol. 36(15_suppl): 9029‑9029.

  7. Torralvo J, Friedlaender A, Achard V, Addeo A (2019) The activity of immune checkpoint inhibition in kras mutated non-small cell lung cancer: a single centre experience. Cancer Genomics Proteomics 16(6):577–582

    Article  CAS  Google Scholar 

  8. Lee CK, Man J, Lord S, Cooper W, Links M, Gebski V et al (2018) Clinical and molecular characteristics associated with survival among patients treated with checkpoint inhibitors for advanced non-small cell lung carcinoma: a systematic review and meta-analysis. JAMA Oncol 4(2):210–216

    Article  Google Scholar 

  9. Nishio M, Barlesi F, West H, Ball S, Bordoni R, Cobo M, et al. (2020). Atezolizumab Plus Chemotherapy for First-Line Treatment of Non-Squamous Non-Small Cell Lung Cancer: Results From the Randomized Phase III IMpower132 Trial. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer.

  10. West H, McCleod M, Hussein M, Morabito A, Rittmeyer A, Conter HJ et al (2019) Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol juill 20(7):924–937

    Article  CAS  Google Scholar 

  11. Herbst RS, Lopes G, Kowalski DM, Kasahara K, Wu Y-L, Castro GD et al (2019) LBA4 Association of KRAS mutational status with response to pembrolizumab monotherapy given as first-line therapy for PD-L1-positive advanced non-squamous NSCLC in Keynote-042. Ann Oncol 30:xi63–xi64

    Article  Google Scholar 

  12. Gadgeel S, Rodriguez-Abreu D, Felip E, Esteban E, Speranza G, Reck M et al (2019) LBA5–KRAS mutational status and efficacy in KEYNOTE-189: Pembrolizumab (pembro) plus chemotherapy (chemo) vs placebo plus chemo as first-line therapy for metastatic non-squamous NSCLC. Ann Oncol 30:xi64–xi65

    Article  Google Scholar 

  13. Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N et al (2018) Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 378(24):2288–2301

    Article  CAS  Google Scholar 

  14. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE et al (2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373(17):1627–1639

    Article  CAS  Google Scholar 

  15. Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J et al (2016) Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet Lond Engl 387(10030):1837–1846

    Article  CAS  Google Scholar 

  16. Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J et al (2017) Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet Lond Engl. 389(10066):255–265

    Article  Google Scholar 

  17. Mazieres J, Drilon A, Lusque A, Mhanna L, Cortot AB, Mezquita L et al (2019) Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol Off J Eur Soc Med Oncol 30(8):1321–1328

    Article  CAS  Google Scholar 

  18. Ng TL, Liu Y, Dimou A, Patil T, Aisner DL, Dong Z et al (2019) Predictive value of oncogenic driver subtype, programmed death-1 ligand (PD-L1) score, and smoking status on the efficacy of PD-1/PD-L1 inhibitors in patients with oncogene-driven non-small cell lung cancer. Cancer 125(7):1038–1049

    Article  CAS  Google Scholar 

  19. Scheel AH, Ansén S, Schultheis AM, Scheffler M, Fischer RN, Michels S et al (2016) PD-L1 expression in non-small cell lung cancer: correlations with genetic alterations. Oncoimmunology 5(5):e1131379

    Article  Google Scholar 

  20. Jeanson A, Tomasini P, Souquet-Bressand M, Brandone N, Boucekine M, Grangeon M et al (2019) Efficacy of Immune checkpoint inhibitors in kras-mutant non-small cell lung cancer (NSCLC). J Thorac Oncol Off Publ Int Assoc Study Lung Cancer 14(6):1095–1101

    CAS  Google Scholar 

  21. Aredo JV, Padda SK, Kunder CA, Han SS, Neal JW, Shrager JB et al (2019) Impact of KRAS mutation subtype and concurrent pathogenic mutations on non-small cell lung cancer outcomes. Lung Cancer Amst Neth juill 133:144–150

    Article  Google Scholar 

  22. Arbour KC, Rizvi H, Plodkowski AJ, Hellmann MD, Knezevic A, Heller G, et al. Treatment Outcomes and Clinical Characteristics of Patients with KRAS-G12C-Mutant Non-Small Cell Lung Cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 8 févr;

  23. Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI et al (2020) KRASG12C inhibition with sotorasib in advanced solid tumors. N Engl J Med 383(13):1207–1217

    Article  CAS  Google Scholar 

Download references

Funding

None.

Author information

Authors and Affiliations

  1. Service de Pharmacie, HUPSSD-APHP, 125, rue de Stalingrad, 93009, Bobigny, France

    Thierry Landre & Claire Davoine

  2. Service de Pneumologie, CHU d’Angers, Angers Cedex 9, France

    Gregoire Justeau

  3. Service de Pneumologie, CHI Créteil, Créteil, France

    Jean-Baptiste Assié & Christos Chouaïd

  4. Servie d’Oncologie, HUPSSD, Hôpital Avicenne, APHP, Bobigny, France

    Kader Chouahnia & Boris Duchemann

  5. Service de Gériatrie, HUPSSD, Hôpital René-Muret, APHP, Sevran, France

    Chérifa Taleb

  6. Inserm U955, UPEC, IMRB, Créteil, France

    Christos Chouaïd

Authors
  1. Thierry Landre
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gregoire Justeau
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jean-Baptiste Assié
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kader Chouahnia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Claire Davoine
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chérifa Taleb
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christos Chouaïd
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Boris Duchemann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thierry Landre.

Ethics declarations

Conflict of interest

The authors declare that there is no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 42 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Landre, T., Justeau, G., Assié, JB. et al. Anti-PD-(L)1 for KRAS-mutant advanced non-small–cell lung cancers: a meta-analysis of randomized–controlled trials. Cancer Immunol Immunother 71, 719–726 (2022). https://doi.org/10.1007/s00262-021-03031-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-021-03031-1

Keywords

Search

Navigation