Immunotherapy for Lung Cancer – It’s Not for Everyone

Written by Dr. Kaique Filardi

Immunotherapy has sparked a revolution in the fight against solid organ cancers, transforming the landscape of cancer treatment and offering new hope to patients — but it’s not for everyone.

Individuals with lung cancer, whether small cell (SCLC) or non-small cell (NSCLC), are benefiting from immune checkpoint inhibitors, the most widely used form of immunotherapy, which has led to improved survival and quality of life.

However, not all patients respond to immunotherapy, and long-term survival is achieved by only a few. Additionally, some patients may experience immune-related toxicities, with a small percentage suffering from serious complications that can lead to significant morbidity and mortality. 

Dr. Mark Kris, a thoracic oncologist at Memorial Sloan Kettering Cancer Center, stresses the importance of identifying oncogenic drivers to guide treatment decisions rather than defaulting to immunotherapy for all patients.

“One thing we can do is look at the mutations and other kinds of oncogenic drivers, and in those patients, give the treatments that are targeted to those oncogenic drivers and not the immune treatments. So I think that’s the first step in saying who is going to benefit from an immune treatment, make sure that they don’t have a cancer that we can detect in 2024 that is wired in a different way,” he says. 

When is Immunotherapy the Standard?

Dr. Kris says the first step should be testing for these drivers, such as epidermal growth factor receptor mutation (EGFR), anaplastic lymphoma kinase (ALK) rearrangements, and ROS1 rearrangement. 

For patients with tumors harboring a driver mutation, the preferred initial treatment is a targeted inhibitor. If well-tolerated, this therapy is continued until the disease shows signs of progression. Current evidence suggests that immunotherapy-based approaches are not suitable as a first-line treatment for these patients.

On the other hand, in the absence of a driver mutation, immunotherapy should be the standard treatment.

Interestingly, with the advancement of targeted therapy, Dr. Kris points out that in certain cases, oncogenic drivers and immunotherapy can work together, though this remains an exception.

“There are some drivers where immune treatments still have benefit,” Dr. Kris explains, including the KRAS mutation. When a KRAS G12C mutation is present, “there are specific targeted therapies [and patients] also can benefit from immune therapy. They have, I’ll call it the dual wiring there, that you can go and use both modalities.”

The use of immunotherapy also plays an essential role in the context of metastatic disease and toward symptom control. 

“The amazing story of the immune treatments is that they can cure patients with metastatic cancer. …Also, when you give these immune treatments with therapies that have the ability to cure, cancer surgery or radiation or the combination of radiation and chemotherapy, the immune treatment increases the chance of cure, and that is absolutely amazing,” says Dr. Kris.

Next Steps After Immunotherapy Indication

Immunohistochemistry for PD-L1 expression, measured by tumor proportion score, predicts response to immunotherapy in advanced NSCLC without a driver mutation and can be conducted using various validated antibodies.

Once mutation tests, PD-L1 scoring, and histology have been determined, first-line therapy recommendations are:

• For patients with PD-L1 expression <50 percent, the combination of checkpoint inhibitor and platinum-doublet chemotherapy is recommended.
• Patients with PD-L1 expression ≥50 percent are offered therapy with checkpoint inhibitors, with or without platinum-doublet chemotherapy.
• The combination of PD-1/PD-L1 immunotherapy plus anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) immunotherapy is a chemotherapy-sparing alternative.

Key Challenges in Immunotherapy Use

Although immunotherapy offers significant clinical benefits, over 20% of patients experience immune-related adverse events, with the incidence rising to more than 50% when combination therapies are used.

Immune-related adverse events (IAE) differ in their timing of onset, severity, and underlying biological mechanisms. They can impact a wide range of organs and may occur at any point during the patient’s treatment. While they most commonly arise within the first three months of therapy, they have also been observed long after treatment has been discontinued.

Treatment for IAE primarily involves the use of glucocorticoids for acute cases that arise during immune checkpoint inhibitor treatment, often yielding good results within several weeks. While most IAEs resolve, some can progress into a chronic state after immune checkpoint inhibitor therapy has ended, potentially necessitating lifelong treatment, such as hormonal supplementation or ongoing immunosuppression.

In recent years, international guidelines have been published to assist clinicians in managing IAE. Notable among these are the guidelines from the National Comprehensive Cancer Network (NCCN) and the European Society of Medical Oncology (ESMO). 

It is worth noting that prior to starting treatment, risk stratification is essential to identify patients at high risk of IAEs and to prevent exposure to unacceptable levels of risk, reiterating that immunotherapy is not for everyone. 

Contraindications to immunotherapy include connective tissue, rheumatologic, or interstitial lung disease. For patients who have contraindications to immunotherapy, a histology-appropriate platinum doublet may be used.

Emerging Trends in Immunotherapy for Lung Cancer

Recent interest focuses on combining immune checkpoint inhibitors with novel strategies, such as radiation, other immune checkpoint inhibitors, or systemic therapies.

Another crucial research focus in this field is the use of ‘liquid biopsy’ assays to detect patients who are not responding to therapy early in their treatment, allowing for timely adjustments to their treatment plans.