Immunotherapy and Lung Cancer: Longer Survival Despite Serious Side Effects

Over the past 10 years, cancer treatment has been transformed by immunotherapies in the immune checkpoint inhibitor class. Although immunotherapy is known for having fewer side effects than chemotherapy and other cancer medicines, about 15-20% of patients may experience serious immunotherapy-related side effects (grade 3 or higher) . These rates can vary according to the type of immunotherapy and whether it is used alone, as a dual combination or with other chemotherapy.

Recent research shows that patients receiving immunotherapy who develop immune-related side effects and have non-small cell lung cancer (NSCLC) have better overall survival regardless of the severity of those effects. This important finding suggests that difficulties encountered during treatment may have unexpectedly positive implications for patients' long-term survival.

Study Details

JAMA Network Open published this research on January 18, 2024. It found better overall survival among NSCLC patients who developed immunotherapy-related side effects, even when those effects required hospitalization. The study showed that patients with side effects had median overall survival more than twice as long as those without them, with no difference in overall survival between hospitalized patients and those treated as outpatients.

The study included data from 803 patients with locally advanced or metastatic NSCLC who received at least one line of immunotherapy between March 2014 and November 2021. Over a median follow-up of 51.9 months, 37% developed clinically significant immune-related adverse events (irAEs), of whom 30.3% required hospitalization. The most common irAEs were pneumonitis (27.6%), dermatitis (21.2%) and colitis (14.1%).

Clinical Features Associated with irAE Development

The study also identified associations between certain clinical features and the development of immune-related adverse events (irAEs). These features and their statistical significance were as follows:

• Age: Patients aged 60 and older were more likely to develop irAEs (P = 0.05).
• ECOG Performance Status: Patients with an ECOG performance status of 0 had a higher risk of developing irAEs (P < 0.001). ECOG performance status measures how independently a patient can carry out daily activities.
• PD-L1 Level: Patients with higher PD-L1 levels were more likely to develop irAEs (P = 0.05). PD-L1 is a protein level that affects the effectiveness of immunotherapy.
• Bone Metastases: Patients without bone metastases had a higher risk of developing irAEs (P = 0.01).
• Neutrophil-to-Lymphocyte Ratio: Patients with a neutrophil-to-lymphocyte ratio of 3 or less were more likely to develop irAEs (P < 0.001). This ratio reflects the body's inflammatory state and immune response.
• Laboratory Values: Patients with hemoglobin, albumin and lactate dehydrogenase levels within the reference range had a higher risk of developing irAEs (P = 0.03 for hemoglobin, P < 0.001 for albumin and P = 0.007 for lactate dehydrogenase). These values may reflect the patient's overall health and treatment response.

Overall Survival

The study found significantly longer median overall survival among patients who developed irAEs than among those who did not. Median overall survival was 23.7 months in patients with irAEs, compared with 9.8 months in those without irAEs (P < 0.001). In multivariable analysis, developing irAEs retained an independent association with longer overall survival (hazard ratio, 0.53; 95% CI, 0.40-0.70; P < 0.001).

The Effect of Hospitalization

Among patients with clinically significant irAEs, median overall survival did not differ significantly between those hospitalized and those treated as outpatients. Median overall survival was 20.8 months for hospitalized patients and 25.6 months for outpatients (P = 0.33).

Time to Next Treatment

Time to next treatment (TTNT) was also significantly longer among patients with clinically significant irAEs than among those without them. Median TTNT was 18 months with irAEs and 7.3 months without irAEs (P < 0.001). However, among patients with irAEs, median TTNT did not differ significantly between hospitalized patients and outpatients: 15.3 and 15.9 months, respectively (P = 0.67).

Conclusion

This study presents an important finding about immunotherapy for NSCLC. Patients receiving immunotherapy who develop immune-related adverse events (irAEs) have better overall survival regardless of the severity of those events. In particular, median overall survival was significantly longer in patients who developed irAEs than in those who did not. This may also be interpreted as an indicator of response to immunotherapy.

The study also found that the association between irAE development and patient survival did not vary according to the need for hospitalization. This is important for managing irAEs and planning treatment. It further noted that patients responding to treatment were more likely to develop irAEs, another factor to consider when evaluating treatment response.