Immunotherapy for Non-Small Cell Lung Cancer Brain Metastases: Ready for Prime Time

Patients with non-small cell lung cancer (NSCLC) brain metastases and a KRAS mutation — a genotype associated with an especially poor prognosis — who were treated with immune checkpoint inhibitors had a one-year survival rate equivalent to that of patients without the mutation in a large cohort study. This notable finding was reported by a team of Cleveland Clinic researchers in an oral presentation at the Society for Neuro-Oncology Inaugural Conference on Brain Metastases on Aug. 17 in New York.

A second oral presentation from the Cleveland Clinic research team further defined clinical parameters of efficacy of immunotherapy for NSCLC brain metastases, demonstrating that upfront steroid therapy was associated with worsened outcomes and that a high neutrophil-to-lymphocyte ratio was associated with poor prognosis.

“Immunotherapy has brought about a dramatic change in medical treatment for non-small cell lung cancer, one of the deadliest cancers and the most common cause of brain metastases,” says neuro-oncologist Manmeet S. Ahluwalia, MD, Director of the Brain Metastasis Research Program at Cleveland Clinic’s Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center. “Our findings confirm the importance of immunotherapy in treating brain metastases and reveal critical indicators of efficacy.”

Dr. Ahluwalia was the senior investigator for both studies, which drew from a database of 1,000 patients treated at Cleveland Clinic for NSCLC brain metastases between 2012 and 2018. He also served as scientific program co-chair of the conference.

Background: Immune therapy primer

So-called checkpoints are molecules (referred to as “PD-1”) on T cells that can be activated by ligands (referred to as “PD-L1”) presented by other cells to limit an immune response. This is especially important under normal circumstances to minimize the killing of host cells and prevent autoimmune disease. Cancer cells may take advantage of PD-1 checkpoints by activating them themselves, thereby dampening the host immune system and avoiding attack. To this end, some cancer cells express many PD-L1 proteins.

Immune checkpoint inhibitors (ICIs) include monoclonal antibodies that target PD-1 (pembrolizumab, nivolumab) or PD-L1 (atezolizumab) molecules to block cellular protein binding, with the effect of boosting the host immune response.

Study 1: Patients with KRAS mutation are prime candidates for immunotherapy

Of the 1,000 patients in the Cleveland Clinic database, 226 had known KRAS mutational status; 121 of them received at least two cycles of immunotherapy. The KRAS gene acts as an on-off switch to control cell proliferation; KRAS mutations disrupt negative signaling, causing cells to continuously proliferate by recruiting and activating proteins necessary for growth.

The first study from this database examined overall survival according to whether patients had a KRAS mutation or wild-type KRAS and whether or not they received immunotherapy. “Patients with KRAS mutations usually fare worse than patients with wild-type KRAS when treated with chemotherapy, after adjusting for age, Karnofsky Performance Status, lesion number and extracranial metastasis,” Dr. Ahluwalia notes.

Findings of the study, which assessed survival from the start of immunotherapy or the date brain metastasis was diagnosed, included the following.

• Among those treated with immunotherapy, no difference was found in overall survival between patients with KRAS mutations versus wild-type KRAS after adjusting for age, Karnofsky Performance Status, lesion number and extracranial metastasis.
• Among those with KRAS mutations, patients treated with immunotherapy had a higher one-year overall survival rate than those treated with chemotherapy (60.9% vs. 38.7%, respectively; P = 0.05).
• Among those with wild-type KRAS, no one-year survival advantage was found with immunotherapy treatment versus no immunotherapy (61.9% vs. 62.5%; P = 0.85).

The greater benefit with immunotherapy relative to chemotherapy in patients with KRAS mutations may be explained by the fact that these patients were more likely to test positive for PD-L1 expression than were patients with wild-type KRAS (80.1% vs. 61.9%, P = 0.04). Both KRAS and PD-L1 status were known for 109 patients.

“Greater expression of PD-L1 — the target of ICI therapy — sets the stage for immunotherapy to be highly effective,” explains Dr. Ahluwalia. “It actually brings the notoriously poor survival rates associated with KRAS mutations up to the level achieved in wild-type KRAS patients.”

Study 2: Steroid therapy thwarts immunotherapy

The second study examined characteristics and outcomes among the 121 patients who received ICI therapy, whose profile was as follows:

• Median age of 62 years (range, 39-81)
• 86 patients received nivolumab, 25 received pembrolizumab, 7 received atezolizumab and 3 received multiple agents
• 112 patients (92.6%) underwent stereotactic radiosurgery
• 25 patients (20.7%) underwent surgical resection
• 9 patients (7.4%) underwent ICI therapy only
• 24 patients (19.8%) received up-front oral steroids (within the first 28 days of immunotherapy), with a median prednisone-equivalent dose of 27 mg

Evaluation of progression-free and overall survival rates revealed two significant trends. Worse outcomes were seen with:

• Use of oral steroids. Median progression-free survival was 148 days for patients given up-front steroid therapy vs. 301 days in the rest of the cohort (P = 0.0095).
• A high neutrophil-to-lymphocyte ratio (NLR) at the start of immunotherapy. Median overall survival was 337 days in patients with NLR ≥ 5 (n = 33) versus 558 days in patients with NLR < 5 (n = 54) (P = 0.038).

“Steroids are immunosuppressive, so it’s not surprising that they reduce the effectiveness of immune-enhancing ICI therapy,” notes Dr. Ahluwalia.

Regarding the NLR findings, he adds: “Although NLR provides prognostic information, we don’t know whether it impacts the efficacy of therapy or is merely a marker of overall health.”

Takeaways and future directions

Dr. Ahluwalia says two main conclusions can be drawn from this research:

1) For a patient with NSCLC brain metastasis who has a KRAS mutation, immunotherapy is indicated.

2) For patients on immunotherapy who need steroids, minimizing the steroid dose is important.

His research group is now assessing different combinations of therapeutic approaches, such as immunotherapy with radiosurgery, to evaluate efficacy and focus on strategies for reducing steroid use in patients treated with immunotherapy.