Elsevier

Clinical Lung Cancer

Volume 23, Issue 1, January 2022, Pages 60-71
Clinical Lung Cancer

Original Study
EGFR High Copy Number Together With High EGFR Protein Expression Predicts Improved Outcome for Cetuximab-based Therapy in Squamous Cell Lung Cancer: Analysis From SWOG S0819, a Phase III Trial of Chemotherapy With or Without Cetuximab in Advanced NSCLC

https://doi.org/10.1016/j.cllc.2021.10.002Get rights and content

Abstract

Background

The phase III S0819 trial investigated addition of cetuximab to first-line chemotherapy (CT) in NSCLC. Subgroup analyses suggested an OS benefit among patients with EGFR copy number gain in squamous cell carcinomas (SCC), (HR = 0.58 [0.39-0.86], P = .0071). A more detailed model based on EGFR FISH, EGFR IHC and KRAS mutation status was evaluated to yield a more precise predictive paradigm of cetuximab-based therapy in advanced NSCLC.

Methods

FISH was performed using the Colorado Scoring Criteria; H-Score was used to quantify EGFR IHC expression (cut-off ≥ 200). A Cox model was used to assess treatment effects for OS and PFS within biomarker and clinical subgroups. KRAS mutation was analyzed using Therascreen. The false discovery rate controlled for multiple comparisons. S0819 ClinicalTrials.gov Identifier: NCT00946712.

Results

Of 1,313 eligible patients, assay results were obtained for FISH on 976 patients (41% positive), for IHC on 945 patients (31% positive), and KRAS mutation status on 627 patients (26% positive). In SCC patients, OS was significantly improved with addition of cetuximab when both EGFR FISH and EGFR IHC were positive (N = 58), (OS HR: 0.32 [95% CI 0.18-0.59]; P = .0002, q = 0.08), median 12.6 versus 4.6 months. The results were independent of KRAS mutation status. In Non-SCC, no predictive value of EGFR IHC, EGFR FISH status and/or KRAS status was seen.

Conclusions

In NSCLC SCC, a combination index of EGFR FISH plus EGFR IHC results was associated with improved OS when cetuximab was added to CT, representing a potential predictive molecular paradigm for patients suitable for EGFR-antibody therapy.

Introduction

The SWOG S0819 trial1 was an open-label, phase III study, designed to evaluate the efficacy of cetuximab, a highly specific chimeric monoclonal IgG1 antibody targeting EGFR, in addition to carboplatin-paclitaxel or carboplatin-paclitaxel-bevacizumab as first-line treatment for advanced NSCLC. The design of this study has been previously described2 and the primary results have been published.1 Prior to S0819, cetuximab had been investigated in combination with platinum-based chemotherapies for the treatment of CT-naïve patients with advanced NSCLC in unselected patient populations and among patients with higher expression levels by immunohistochemistry.3, 4, 5, 6, 7, 8 Accordingly, the design of S0819 included an evaluation of EGFR by fluorescence in situ hybridization (FISH) as a potential predictive biomarker for cetuximab in this population. To investigate this directly, S0819 included 2 co-primary objectives: a comparison of OS in the entire study population and PFS in patients with an increased gene copy number of EGFR, assessed by FISH. While there were no significant differences in the primary endpoints, secondary analyses suggested that in the sub-population of SCC patients with EGFR FISH-positive (FISH+), OS was significantly improved in the cetuximab-containing arm compared with the control arm, with an HR of 0.58 (95% CI 0.39-0.86; P = .007), median OS of 6.1 months (95% CI 4.2-8.7) and 11.8 months (95% CI 8.6-13.5) in the control and cetuximab-containing arms, respectively. These data suggested that further biomarker analysis was warranted to determine which patients derive benefit from the addition of cetuximab to platinum chemotherapy.

The S0819 study also included a prospective evaluation of KRAS mutation status, a factor highly relevant to the success of EGFR-directed antibodies in colorectal cancer.9 KRAS mutations are rare in lung SCC histology, but frequent in lung non-SCC (>25%).10 Evaluation of KRAS status was incorporated into S0819 to determine whether it played a similar predictive role in lung non-SCC cases.

Here, we evaluated the impact of EGFR protein expression and copy number, along with KRAS mutation status, on patient outcome in the S0819 clinical trial, the largest randomized study of cetuximab plus chemotherapy conducted to date.

Section snippets

Study Design

The S0819 study design, characteristics, arm treatments, and eligibility criteria have been previously reported.1, 2 This was a randomized, multicenter, phase III trial of carboplatin + paclitaxel or carboplatin + paclitaxel + bevacizumab with or without concurrent cetuximab in patients with histologically or cytologically proven stage IV primary NSCLC that was newly diagnosed or recurrent after previous surgery and/or radiation. A co-primary objective of the study was to evaluate clinical

Results

From August 13, 2009 to May 30, 2014, 1,333 patients were enrolled in the study; 20 were deemed ineligible, resulting in 1,313 patients in the intention-to-treat (ITT) population: CT plus cetuximab arm (N = 656) and CT without cetuximab arm (N = 657) (Figure 1). A description of the full patient population and the population characteristics within the biomarker-defined subgroups is presented in Table 1. Of the 1313 eligible patients, EGFR FISH was available for 976 patients (74%), EGFR IHC was

Discussion

The S0819 trial assessed the efficacy and safety of carboplatin/paclitaxel, with bevacizumab in non-SCC histology, with or without cetuximab in the first-line treatment of patients with advanced NSCLC. While the addition of cetuximab did not result in a statistically significant difference in OS in the entire study population, or in PFS in the EGFR FISH+ patients (primary endpoints), analyses presented here indicate a significant benefit with cetuximab treatment in SCC patients who had a

Conclusion

Despite recent advances in personalized therapy for lung cancer, lung SCC remains largely excluded from targeted therapy approaches, with the rare exception of those who are never-smokers with oncogene-driven disease. Our results suggest that leveraging the recognized high expression of WT EGFR by a FISH/IHC combination index could provide a step forward toward personalizing therapy with EGFR-directed monoclonal antibody therapy. Further prospective validation studies of this concept are

Acknowledgment

This work was supported by the National Cancer Institute of the National Institutes of Health [U10CA180888, U10CA180819, U10CA180846]; and in part by Eli Lilly and Company. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or Eli Lily and Company.

Disclosure

Fred R. Hirsch has participated in scientific advisory boards (compensated) for Bristol-Myers Squibb, Amgen, Merck, Novartis, Genentech/Roche, Sanofi, Genzyme, AstraZeneca/Daiichi, Lilly, Abbvie, and OncoCyte. Francesco Agustoni received honoraria from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, and Astra Zeneca, travel/meeting support from Incyte, and has participated in scientific advisory boards for Boehringer-Ingelheim, Merck Sharp & Dohme, and Bristol-Myers Squibb. Roy S. Herbst

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    • Cited by (5)

    a

    F.R.H. and M.W.R. contributed equally to this work as first authors.

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