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Efficacy-Effectiveness Gap in Immunotherapy Clinical vs. Real-World Data

A recent study published in Scientific Reports aimed to assess how outcomes of immunotherapy in real-world (effectiveness) parallel to outcomes in clinical trial (efficacy) data. The researchers also investigated factors that might explain an efficacy-effectiveness gap in stage IV non-small cell lung cancer.

Stage IV non-small cell lung cancer (NSCLC)

In randomized clinical trials (RCTs) immune checkpoint inhibitors (ICI) have demonstrated promising results in disease progression and survival for patients with stage IV NSCLC. There are currently three FDA and EMA approved programmed cell death protein-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors available for the treatment of stage IV NSCLC. These include, nivolumab (anti-PD-1), pembrolizumab (anti-PD-1) and atezolizumab (anti PD-L1). However, the results from RCTs are not easily generalisable to clinical practice due to the strict eligibility criteria. Most patients included in RCTs are under 65, despite age being associated with increased risk of lung cancer. Additionally, NSCLC patients with comorbidities, such as auto-immune diseases, are often not eligible for participating in RCT.

Presently, RCTs are still the standard to prove the efficacy of new oncology therapies. Consequently, there could be a gap in the efficacy demonstrated in RCTs and the effectiveness of therapies in clinical practice.

Assessing the efficacy-effectiveness gap

The researchers behind this study had previously demonstrated that the survival of patients with metastatic NSCLC treated with chemotherapy or targeted therapy is nearly one-quarter shorter in real-world practice than for patients induced in trials. For immunotherapy in metastatic NSCLC, some efforts have been made to assess the possible efficacy-effectiveness gap. Most studies reported comparable outcomes in real-world compared to those observed in clinical trials. However, previous studies have not discriminated between drug type, nor compared survival curves to detect potential differences between survival dynamics in real-world and trial data. Furthermore, patient characteristics have not been compared with trial cohorts in the search for factors to explain any efficacy-effectiveness gap.

Therefore, the researchers aimed to assess how clinical outcomes of specific immunotherapy drugs for patients with stage IV NSCLC in real-world data compared to the data produced from clinical trials. They also investigated factors that might explain any observed efficacy-effectiveness gap.

Observed efficacy-effectiveness gap

For the patient dataset, all patients diagnosed with stage IV NSCLC in 2015-2018 in six Dutch teaching hospitals were identified and followed-up with from the date of diagnosis until death or end of data collection. Progression-free survival (PFS) and overall survival (OS) from first-line (1L) pembrolizumab and second-line (2L) nivolumab were compared with clinical trial data by calculating hazard ratios (HRs).

From a total of 1,950 patients, 1005 (52%) started with any 1L treatment, of which 83 received pembrolizumab. Nivolumab was started as 2L treatment for 141 patients. For both settings, PFS times were comparable between real-world and RCT, with a HR of 1.08 and 0.91, respectively. It was observed that OS was found to be significantly shorter in real-world for 1L pembrolizumab. Moreover, receiving subsequent lines of treatment was less frequent in real-world compared with RCT.

There was no efficiency gap for PFS from immunotherapy in patients with stage IV NSCLC. However, there was a gap for OS with 1L pembrolizumab in real-world compared to clinical trial data, which could be explained by fewer patients proceeding to a subsequent line of treatment in real-world.


This study identified an efficacy-effectiveness gap in overall survival for 1L pembrolizumab. It was also identified that fewer patients proceed to a subsequent line of treatment in real-world compared with clinical. Thus, this study went beyond previous research by identifying possible reasons for observed gaps in efficacy and effectiveness. Overall, this research shows that PFS and OS results from clinical trials can differ in generalisability to real-world studies. Therefore, when considering the effectiveness of a drug, investigators must consider how it performs long term by observing real-world data.

Image credit: topntp26 – FreePik

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Cancer / Clinical Trials / Real World Data

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