Biomarker Hunt Garners Interest Amid New Standard of Care in NSCLC

Terence M. Williams, MD, PhD

With the emergence of a new standard of care in stage III non—small cell lung cancer (NSCLC), the hunt for predictive and prognostic biomarkers remains an area of unmet clinical need, said Terence M. Williams, MD, PhD.

"Investigating biomarkers in lung cancer develops an integrated understanding of all the risk factors that impact a patient's survival and recurrence of their disease," said Williams. "It is important for us to provide patients with the most information about their individual risks to allow patients to make the best decisions."

In February 2018, the FDA approved durvalumab (Imfinzi) for the treatment of patients with unresectable, stage III NSCLC whose disease has not progressed following concurrent platinum-based chemoradiation, based on initial data from the phase III PACIFIC trial. In July 2019, the label was updated to include overall survival (OS) results from the trial, which demonstrated a 32% reduction in risk of death with durvalumab compared with placebo.¹

Moreover, investigators are actively exploring biomarkers that could determine benefit to immunotherapy and other therapeutic approaches, including stereotactic body radiation (SBRT). Williams was involved in 2 studies investigating the clinical utility of neutrophil-to-lymphocyte ratio (NLR) and serum bicarbonate as prognostic biomarkers for patients with localized NSCLC who previously received SBRT.^2,3

Pre-treatment NLR >3.6 was confirmed to be associated with worse prognosis for patients with localized NSCLC who received SBRT, while pre-treatment serum bicarbonate was found to be predictive for primary tumor control in the same patient population. Importantly, serum bicarbonate may predict risk of disease recurrence.

"We are extending our studies into more locally advanced stage II or III NSCLC," said Williams. "Additionally, we are looking at other types of biomarkers—not just in the blood, but in the tumor tissue. If there is tumor tissue available, biopsy could provide DNA and RNA—based information that would let us predict recurrence after chemoradiation."

In an interview during the 2020 OncLive^® State of the Science Summit™ on Lung Cancer, Williams, principal investigator at the Williams Lab at the Ohio State University Comprehensive Cancer Center—James, discussed the impact of the PACIFIC trial on stage III NSCLC and how the hunt for prognostic biomarkers is underway across the lung cancer paradigm.

OncLive^®: What regimens are in development? How could they impact treatment?

Williams: The current standard of care for patients with a performance status of 0 to 1 is chemoradiation at 60 Gy in 30 fractions with a doublet chemotherapy regimen, such as carboplatin/paclitaxel or cisplatin/etoposide.

Following the end of chemoradiation, based on the results of the PACIFIC trial, patients will receive durvalumab for up to 1 year if they are able to tolerate it and their disease does not progress.

That is our current standard, and many people are looking to build upon that by moving immunotherapy to coincide with the delivery of chemoradiation during the initial 6 weeks of treatment.

In addition, some people are looking to add more immunotherapy drugs before or after chemoradiation. Others are using novel drugs that target DNA repair pathways in combination with chemoradiation. Some examples that are being conducted in Europe are looking at certain DNA repair inhibitors targeting PARP, ATR, or ATM.

Others are looking at the use of different types of radiation treatment, such as proton therapy, as a means to reduce the normal tissue toxicity from radiation.

Could you discuss your study on pre-treatment NLR in NSCLC?

We recently published our institutional experience looking at a serum biomarker called NLR. That measures the number of neutrophils in the blood compared with the number of lymphocytes. In patients who have a more inflamed, poorly immunogenic, tumor environment, higher NLR correlates with worse outcomes, particularly regarding overall survival (OS).

Through our study, we showed that having a high NLR predicted for worse outcomes [to SBRT]. The patient population we studied was early-stage lung cancer—mainly patients with stage I disease—who received SBRT.

How could these study results impact this patient population?

This study has not directed changed patient care, although we are arguing that this could be a potentially useful biomarker to predict which patients are more likely to die from their cancer. It could be used in predictive modeling to generate a nomogram score, which could assess risk of dying from stage I lung cancer.

Currently, it is more of a prognostic biomarker than anything else. We would like to validate that on additional data sets, particularly in clinical trials. There are also data suggesting that the use of NLR can predict response to immunotherapy. Our study did not look at that, but it is another aspect that could be addressed.

What potential benefit could this tool have on patients upon diagnosis?

Knowing a patient's NLR could provide some insight into whether or not a patient should forgo radiation. For example, if a patient has a life expectancy of less than 2 years, and if their tumor is large and near the center part of their chest, it may be reasonable for them not to receive radiation as the risk of toxicity may be higher.

It could give patients an assessment of [their morbidity risk] based on our results, age, performance status, and comorbidities. With those factors in mind, the patient can decide whether they want to proceed with therapy or not.

You were also part of another study looking at pre-treatment serum bicarbonate in the same patient population. Could you discuss the implications from those findings?

That was a similar study trying to identify easy biomarkers that we can use to predict prognosis. This study was more focused on clinical outcomes. while the NLR study focused on OS. NLR did not appear to predict recurrence after SBRT. However, we found that serum bicarbonate did predict for tumor recurrence after radiation quite well.

The advantages of this serum biomarker are that it is readily attainable from blood samples, easy to calculate, and part of a routine laboratory test we normally do as part of a chemistry panel.

The use of this biomarker will allow us to inform patients of their risk of recurrence to help guide them in choosing chemoradiation, surgery, or if they are not a surgical candidate, to consider getting additional therapy.

References

1. Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379(24):2342-2350. doi: 10.1056/NEJMoa1809697
2. Sebastian N, Wu T, Bazan J, et al. Pre-treatment neutrophil-lymphocyte ratio is associated with overall mortality in localized non-small cell lung cancer treated with stereotactic body radiotherapy. Radio & Oncol. 2019. 134:151-157. doi: 10.1016/j.radonc.2019.01.032
3. Sebastian N, Wu T, Driscoll E, et al. Pre-treatment serum bicarbonate predicts for primary tumor control after stereotactic body radiation therapy in patients with localized non-small cell lung cancer. Radio & Oncol. 2019. 140:26-33. doi: 10.1016/j.radonc.2019.05.014