Hypothetical target trial emulation assessing of combination pembrolizumab with chemotherapy in NSCLC with frail patients

Abstract

Real-world data (RWE) may enable the investigation of patients who are ineligible for Randomized Controlled Trials (RCT) due to poor performance status, old age, or comorbidities. In addition, it permits research that may be impossible through prospective design due to ethics or feasibility. Hypothetical target trial emulation(hTTE) has emerged as a new method that uses RWD to evaluate new drugs' effectiveness.

This study aimed to assess the effectiveness of combining pembrolizumab and chemotherapy compared with chemotherapy alone in improving overall survival among frail patients with non-small cell lung cancer (NSCLC). Furthermore, we compared our findings with the Keynote-189, which employed the RCT approach. In this study, we utilized data from the Cancer Registry of Norway (CRN) on patients diagnosed with NSCLS during 2015-2021 and the Norwegian Patient Registry (NPR).

We used the Kaplan-Meier method to calculate the median overall survival rate of frail NSCLC patients and the log-rank test to assess the difference between control and active groups. Furthermore, Cox regression models were employed to estimate the hazard ratio (HR).

Data were available for 185 patients, of whom 53.7 % were males. The median age was 68 years. Regarding PD-L1 expression, 33.5% had PD-L1 status < 1, 25.4% had between 1 and 49, and 9.1% had ≥50. The histological types included 81.6% adenocarcinoma,4.3% large cell carcinoma, and 14.6% other types of NSCLC. The Eastern Cooperative Oncology Group (ECOG) performance status was 2 for 80.5% of the study population and above 2 for 19.5%. The median survival was eight months for patients in the control group (receiving chemotherapy alone) and six months for those in the active group (receiving treatment with a combination of pembrolizumab and chemotherapy). However, the difference between the control and active groups is non-significant p=0.8.

Compared to chemotherapy alone, the effectiveness of combination treatment is not significant for frail NSCLC patients who lack genetic variation in Epidermal growth factor receptor (EGFR) or Anaplastic lymphoma kinase (ALK). In conclusion, this study suggests that pembrolizumab combined with chemotherapy has a sub-optimal clinical benefit in NSCLC with frail patients.