Best therapy for people with advanced non-small cell lung cancer who have not been treated without a targetable mutation and moderately impaired performance status

Key messages

– The preferred chemotherapy for people with moderately impaired performance status (PS) with advanced non-small cell lung cancer (NSCLC) and that have never received any treatment before should contain two medicines, one of which is a platinum-based medicine.

– Although the risk for bone marrow damage is higher with a platinum-based medicine, these events are often relatively mild and easy to treat.

– We were unable to assess the effects of immunotherapy on moderately impaired people.

What is non-small cell lung cancer?

Lung cancer is the most frequent cause of cancer-related death worldwide and NSCLC is the most common subtype. At the time of diagnosis, the disease has already spread in more than half of all cases. In the tumors of a minority of people diagnosed with NSCLC that has spread to other parts of the body specific mutations can be found, which are treated distinct from the majority of people without such mutations.

How can non-small cell lung cancer be treated?

NSCLC can only be treated with life-prolonging medicines such as chemotherapy (a medicine used to destroy cancer cells) or immunotherapy (a medicine that boosts the person's immune system and helps the body find and destroy cancer cells). Selecting the best treatment depends on the health condition of the person. That condition is determined using a scale from 0 (no symptoms) to 5 (dead). There is no discussion on the treatment of relatively fit people (scoring 0 or 1), as they often tolerate these treatments relatively well. People with a low health condition (scoring 3 or 4) receive only supportive care in most cases. However, although representing 20% to 30% of all people, the best treatment for moderately impaired people (PS 2) is not clear, as they often do not participate in trials.

What did we want to find out?

Our objective was to investigate the best therapy for people with advanced NSCLC without a specific mutation with PS 2.

What did we do?

We searched medical databases for clinical trials comparing treatments for advanced NSCLC with best supportive care or other treatments.

What did we find?

We found 22 trials; 20 compared different types of chemotherapy and two compared chemotherapy versus immunotherapy.

Main results

People treated with chemotherapy regimens using two medicines, including a platinum-based medicine, had longer survival than people treated with chemotherapies without a platinum-based medicine. However, these people did have more side effects, especially with a negative influence on the bone marrow (matter found in the center of bones), resulting in a temporary lack of red and white blood cells, and platelets. The few studies that analyzed health-related quality of life all used different methods of measurement. We found no difference in quality of life when we looked at those studies individually. We found two partly published trials studying immunotherapy, which found no survival benefit compared to chemotherapy.

What are the limitations of the evidence?

We are moderately confident in our results that chemotherapies with a platinum-based medicine increases survival. We are also moderately confident in the evidence evaluating the time to progression of disease because in all included studies, both investigators and trial participants were fully aware of which treatment the participants received. This might lead to substantial bias. In addition, we have little confidence in the evidence regarding toxicities because the evidence is based on a small number of studies with conflicting outcomes.

How up to date is this evidence?

The evidence is up to date to 17 June 2022.

Authors' conclusions: 

This review showed that as a first-line treatment for people with PS 2 with advanced NSCLC, platinum doublet therapy seems to be preferred over non-platinum therapy, with a higher response rate, PFS, and OS. Although the risk for grade 3 to 5 hematologic toxicity is higher, these events are often relatively mild and easy to treat. Since trials using checkpoint inhibitors in people with PS 2 are scarce, we identified an important knowledge gap regarding their role in people with advanced NSCLC and PS 2.

Read the full abstract...

Most people who are newly diagnosed with non-small cell lung cancer (NSCLC) have advanced disease. For these people, survival is determined by various patient- and tumor-related factors, of which the performance status (PS) is the most important prognostic factor. People with PS 0 or 1 are usually treated with systemic therapies, whereas people with PS 3 or 4 most often receive supportive care. However, treatment for people with PS 2 without a targetable mutation remains unclear. Historically, people with a PS 2 cancer are frequently excluded from (important) clinical trials because of poorer outcomes and increased toxicity. We aim to address this knowledge gap, as this group of people represents a significant proportion (20% to 30%) of the total population with newly diagnosed lung cancer.


To identify the best first-line therapy for advanced lung cancer in people with performance status 2 without a targetable mutation or with an unknown mutation status.

Search strategy: 

We used standard, extensive Cochrane search methods. The latest search date was 17 June 2022.

Selection criteria: 

We included randomized controlled trials (RCTs) that compared different chemotherapy (with or without angiogenesis inhibitor) or immunotherapy regimens, specifically designed for people with PS 2 only or studies including a subgroup of these people.

Data collection and analysis: 

We used standard Cochrane methods. Our primary outcomes were 1. overall survival (OS), 2. health-related quality of life (HRQoL), and 3. toxicity/adverse events. Our secondary outcomes were 4. tumor response rate, 5. progression-free survival, and 6. survival rates at six and 12 months' treatment. We used GRADE to assess certainty of evidence for each outcome.

Main results: 

We included 22 trials in this review and identified one ongoing trial. Twenty studies compared chemotherapy with different regimens, of which 11 compared non-platinum therapy (monotherapy or doublet) versus platinum doublet. We found no studies comparing best supportive care with chemotherapy and only two abstracts analyzing chemotherapy versus immunotherapy.

We found that platinum doublet therapy showed superior OS compared to non-platinum therapy (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.57 to 0.78; 7 trials, 697 participants; moderate-certainty evidence). There were no differences in six-month survival rates (risk ratio [RR] 1.00, 95% CI 0.72 to 1.41; 6 trials, 632 participants; moderate-certainty evidence), whereas 12-month survival rates were improved for treatment with platinum doublet therapy (RR 0.92, 95% CI 0.87 to 0.97; 11 trials, 1567 participants; moderate-certainty evidence). PFS and tumor response rate were also better for people treated with platinum doublet therapy, with moderate-certainty evidence (PFS: HR 0.57, 95% CI 0.42 to 0.77; 5 trials, 487 participants; tumor response rate: RR 2.25, 95% CI 1.67 to 3.05; 9 trials, 964 participants).

When analyzing toxicity rates, we found that platinum doublet therapy increased grade 3 to 5 hematologic toxicities, all with low-certainty evidence (anemia: RR 1.98, 95% CI 1.00 to 3.92; neutropenia: RR 2.75, 95% CI 1.30 to 5.82; thrombocytopenia: RR 3.96, 95% CI 1.73 to 9.06; all 8 trials, 935 participants).

Only four trials reported HRQoL data; however, the methodology was different per trial and we were unable to perform a meta-analysis.

Although evidence is limited, there were no differences in 12-month survival rates or tumor response rates between carboplatin and cisplatin regimens. With an indirect comparison, carboplatin seemed to have better 12-month survival rates than cisplatin compared to non-platinum therapy.

The assessment of the efficacy of immunotherapy in people with PS 2 was limited. There might be a place for single-agent immunotherapy, but the data provided by the included studies did not encourage the use of double-agent immunotherapy.