Atezolizumab with SABR for high-risk early-stage NSCLC: initial results

New results from a phase 1 trial of adding checkpoint inhibitor atezolizumab either prior to, concurrent with, or following stereotactic ablative radiation therapy (SABR) to treat medically inoperable early-stage non-small cell lung cancer (NSCLC) indicate that this combination is not only safe and tolerable, but early efficacy indicators look promising. Our journalist interviews one of the study’s principle investigators, Prof. Arta Monjazeb (Radiation Oncologist, UC Davis).

Prof. Karen Kelly, Medical Oncologist at UC Davis and head of the Lung Committee at SWOG, was the presenting author at the Virtual ASCO Annual Meeting held 29-31 May 2020 [1]. The phase 1 study  was based on the rationale that although stereotactic ablative radiation therapy (SABR) is the standard-of-care for medically inoperable early stage NSCLC, regional and distant failures remain problematic [2]. Because preclinical data has demonstrated some synergy between radiation an immune checkpoint inhibitors, the researchers proposed to see whether neoadjuvant delivery of checkpoint blockade may improve outcomes when compared to adjuvant-only delivery [3,4]. To that end, this phase 1 study was designed to determine the safety, tolerability, and the maximum tolerated dose of neoadjuvant, concurrent, and adjuvant atezolizumab with SABR for high-risk early-stage NSCLC.

The primary objective of the study was to determine the maximum-tolerated dose (MTD) of atezolizumab plus SABR. Key secondary endpoints were to characterize the safety profile of this regimen and to provide preliminary efficacy data to determine the objective response rate (ORR) and disease-free survival. Some exploratory objectives intended to analyze serial blood samples for immuno-phenotyping of peripheral blood mononuclear cells, in addition to tumor-infiltrating immune cells. Furthermore, pretreatment tumor tissue was evaluated for PD -L1 expression and other molecular markers for tumor microenvironment. Serial stool samples were also collected to detect changes in the gut microbiome.

MTD was not reached (n=20), and 5 patients continued in the expansion cohort; therefore the primary endpoint was met. Anemia was the most common adverse event and that was almost exclusively seen as a grade 1 event. The only grade 3 events observed were liver function abnormality (n=1), lymphopenia (n=3), rash (n=1), and musculoskeletal complaints (n=2). No grade 3 pneumonitis was reported. The authors concluded that the recommended phase 2 dose of atezolizumab should be the standard dose of 1200 mg IV.

With regard to efficacy, 4 patients (22%) had partial responses, although these were unconfirmed. Median progression-free survival (PFS) was 25.5 months (95% CI 16.1-not reached). When patients were stratified by their tumor PD-L1 expression status, there appeared to be a trend favoring patients with PD-L1+ tumors; PFS was 30.0 months (95% CI 14.7-not reached) in PD-L1+ versus 16.3 months (95% CI 15.5-not reached) for PD-L1- tumors. The authors concluded that PD-L1 expression may predict early responsiveness, although longer-term follow-up and a randomized trial design is necessary to predict which patients will gain benefit from the addition of immunotherapy and which patients should be treated with radiation alone.

The study demonstrated that atezolizumab administered before, during, and after SBRT was feasible and well tolerated. Antitumor activity was observed with two doses of atezolizumab; initial correlative studies indicate that an inflamed tumor microenvironment may be associated with response. This combination is being tested in the recently activated randomized phase three trial SWOG/NRG S1914, in which that primary endpoint being tested is overall survival.

Our journalist asked the study’s senior investigator Prof. Arta Monjazeb, radiation oncologist at UC Davis, for his perspective:

“The basic premise of this study was that patients with medically inoperable early-stage lung cancer are generally treated with SBRT, which actually does a very good job of achieving local control of these early-stage lung lesions. We also know that these patients don't have very good options for systemic therapy because they have been deemed medically inoperable, meaning that they are generally patients who wouldn't be able to tolerate chemotherapy. While we know that radiation is very good at controlling the local tumor, we also know that there is a subset of patients who fail distally. So the question was: is there anything we can do to improve the outcomes for these patients? If chemotherapy isn't a great option, and so that's where immunotherapy comes in because we know it's effective against lung cancer, but we also know it doesn't carry with it the same type of toxicity that chemotherapy does. That was really the basis for doing the trial.”

“The primary endpoint of this trial was safety, and we were able to meet our safety endpoints. The treatment was well-tolerated, and it didn't really have any unexpected toxicities. Additionally, we gained some preliminary insight into the efficacy of the treatment in these early-stage patients. A number of patients showed early responses to the atezolizumab, even before they received the SBRT. These initial responses may indicate that even in these early-stage medically inoperable lung cancer patients, a systemic effect of the treatment can be observed, supporting the hypothesis that this may be an effective way for us to address microscopic systemic disease in these patients.”

“I anticipate that if the ongoing phase 3 trials end up being positive, then we will see a shift in the standard of care for medically inoperable early-stage lung cancer from SBRT alone to SBRT plus immunotherapy.”

1. Kelly K, et al. Atezolizumab plus stereotactic ablative therapy for medically inoperable patients with early-stage non-small cell lung cancer (NSCLC), ASCO 2020, Abstract 9011.
2. Timmerman R, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA. 2010;303(11):1070-1076. doi:10.1001/jama.2010.261
3. Young KH, et al. Optimizing Timing of Immunotherapy Improves Control of Tumors by Hypofractionated Radiation Therapy. PLoS One. 2016;11(6):e0157164. Published 2016 Jun 9. doi:10.1371/journal.pone.0157164
4. Dovedi SJ, et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res. 2014;74(19):5458-5468. doi:10.1158/0008-5472.CAN-14-1258

Posted on 13 April, 202116 April, 2021