Multigene expression profile for predicting efficacy of cisplatin and vinorelbine in non-small cell lung cancer

Background

There is a need for biomarkers to predict efficacy of adjuvant chemotherapy in resected non-small cell lung cancer (NSCLC). Presented is a combined cisplatin and vinorelbine marker from a previously validated model system [1] tested in two cohorts.

Methods

The profiles consist of correlated in vitro cytotoxicity of cisplatin and vinorelbine and mRNA expressions. Then each profile is correlated to mRNA expression of 3500 tumors. The cohorts are 1) a publically available dataset with 133 completely resected stage Ib-II NSCLC patients, 71 of whom received adjuvant cisplatin and vinorelbine (ACT) and 62 patients who had no adjuvant treatment (OBS) [2] and 2) 95 stage Ib-IIIb completely resected NSCLC patients who all received adjuvant cisplatin and vinorelbine [3]. Endpoint is cancer specific survival.

Results

The combined cisplatin and vinorelbine profiles scored as a continuous covariate showed 1) a Hazard Ratio (HR) of 0.265 ((95% CI:0.079-0.889), p = 0.032) in the ACT cohort (sensitive versus resistant), and no significant discrimination in the OBS cohort (HR = 1.328 (95% CI:0.46-3.835), p = 0.60). A multivariate model adjusted for stage demonstrated significance for ACT (HR = 0.284 (95% CI:0.086-0.944), p = 0.040) but not for OBS (HR = 1.702 (95% CI: 0.575-5.036), p = 0.34). The combined profiles resulted in 2) a significant prediction for up to 3 years from surgery (HR = 0.143 (95% CI:0.038-0.542), p = 0.004, scored as a continuous covariate). A multivariate model adjusting for stage showed that the predictor remained significant (HR = 0.123 (95% CI:0.030-0.512), p = 0.004). A pooled analysis of the two treated cohorts resulted in a significant prediction (HR = 0.187, (95% CI:0.069-0.508), p = 0.001) up to 3 years from surgery using a random effects model.

Conclusions

The combined profiles demonstrate that NSCLC patients who benefit from cisplatin and vinorelbine can be identified. The profiles did not discriminate patients in the untreated arm. This holds promise for a predictive effect of the profiles and it is currently being validated in a prospective study [4]. [1] PLoS ONE 2016, 11(2): e0148070. [2] Zhu et al JCO 2010;28:4417-4424. [3] ASCO 2016 abstract e20007. [4] AACR 2016 Abstract CT154.

Clinical trial identification

Danish Trial Protocol Number H-B-2007-099

Legal entity responsible for the study

Medical Prognosis Institute, Hoersholm, Denmark Dept. of Oncology, Rigshospitalet, Copenhagen, Denmark

Funding

Medical Prognosis Institute, biotech company Markedsmodningsfonden Kræftens Bekæmpelse

Disclosure

I.K. Buhl: Employment: Medical Prognosis Institute. I.J. Christensen: Consulting or Advisory Role: Medical Prognosis Institute. E. Santoni-Rugiu: Honoraria: Novartis; Pfizer; Roche Pharma AG Consulting or Advisory Role: Pfizer Travel, Accommodations, Expenses: Pfizer; Roche Pharma AG.

J. Ravn: Stock and Other Ownership Interests: Novo Nordisk. A. Hansen, T. Jensen, P.B. Jensen, S. Knudsen: Employment: Medical Prognosis Institute Leadership: Medical Prognosis Institute Stock and Other Ownership Interests: Medical Prognosis Institute. J. Askaa: Employment: Medical Prognosis Institute Stock and Other Ownership Interests: Medical Prognosis Institute. J.B. Soerensen: Honoraria: Lilly; Pfizer; Roche Pharma AG Consulting or Advisory Role: Roche Pharma AG Travel, Accommodations, Expenses: Roche Pharma AG.