Atezolizumab plus stereotactic ablative therapy for medically inoperable patients with early-stage non-small cell lung cancer.

Abstract

9011 Background: Stereotactic ablative radiation therapy (SABR) is the standard-of-care for medically inoperable, early stage non-small cell lung cancer (NSCLC), but regional and distant failures remain problematic. Based on our in vivo data showing synergy between radiation and immune checkpoint inhibitors (ICI) and the known efficacy and mild toxicity profile of ICI in NSCLC, we conducted a phase I study to determine the maximum tolerated dose of neoadjuvant, concurrent, and adjuvant atezolizumab with SABR for early stage NSCLC patients (pts). Methods: Eligible pts had histologically confirmed T1-3 NSCLC with at least one feature predictive of increased recurrence risk: diameter ≥1 cm, SUV ≥6.2 on PET, or moderately/poorly differentiated histology, were medically inoperable or refused surgery and had a Zubrod PS ≤2. Patients received 6 cycles of atezolizumab. A 3+3 dose finding design was employed with 3 dose levels: 3 mg/kg, 10 mg/kg, and 1200 mg flat dosing. SABR was delivered starting cycle 3 to 50 Gy over 4-5 fractions. Dose limiting toxicity (DLT) was assessed during the first 9 weeks. Results: 20 pts were enrolled, 15 pts in the dose finding and 5 pts at the recommended phase II dose (RP2D). Patient factors: MedIan age 77; 45% male, 85% smoking history, 85% PS 0-1 and 35% squamous. One pt on dose level 2 had a DLT – a grade 3 rash. Atezolizumab 1200 mg flat dosing was the RP2D. Grade 3 pneumonitis was not observed. Partial responses after 2 cycles were seen in 3/17 evaluable pts (18%) and 1 pt had a minor response. No patient progressed on treatment. PD-L1 expression was 0% 8/13 (62%), >1% - 50% 4/13 (31%), >50% 1/13 (8%) in pts with sufficient tissue. Of 5 pts with PD-L1 expression 3 (60%) were responders and 1 (12.5%) of 8 pts with 0% PD-L1 expression responded. Multi-plex Quantitative Immunofluorescence (QIF) using a T cell activation panel demonstrated to correlate with ICI response was performed on 9 samples (including 2 responders, 1 minor responder). The CD3 QIF score was > two-fold higher in the responders compared to non-responders, and the levels of proliferating and activated T cells were likewise > two-fold higher. Comprehensive stool and serial blood analyses have been completed. Correlative endpoints will be reported along with additional efficacy outcomes. Conclusions: Atezolizumab plus SABR is feasible, safe and shows an efficacy signal in medically inoperable early stage NSCLC. This combination will be tested in a randomized phase III trial SWOG/NRG S1914. Funding: This work was supported by the DOD CDMRP W81XWH-15-2-0063 and Genentech. Clinical trial information: NCT02599454.

SBRT combined with PD-1/PD-L1 inhibitors in NSCLC treatment: a focus on the mechanisms, advances, and future challenges

“…Notably, the substantially improved PFS was associated with an increased TIL score, the presence of an immune-related adverse event, and relative T cell activation status. Moreover, a phase I study conducted by Kelly et al explored the efficacy and safety of atezolizumab plus SBRT for patients with medically inoperable early-stage NSCLC [ 69 ]. The preliminary results updated in the 2020 ASCO indicated that the combination treatment was a feasible choice with no significant additional toxicities.…”

Combination of Immune Checkpoint Inhibitors and Radiotherapy for Advanced Non-Small-Cell Lung Cancer and Prostate Cancer: A Meta-Analysis

“…A phase I study conducted by Kelly et al explored the efficacy and safety of atezolizumab plus stereotactic ablative radiation therapy (SBRT) for medically inoperable patients with early-stage NSCLC. The preliminary results showed that the combined treatment was a feasible option without obvious additional toxicity [ 14 ]. Moreover, the results of phase II prospective trial in patients with metastatic NSCLC reported that the combination of SBRT with concurrent pembrolizumab led to increased PFS, with a systemic response rate of 9.52% and a DCR of 57.14% [ 15 ].…”

The role of immunotherapy in combination with oligometastasis-directed therapy: a narrative review

“…Moreover, the results of ongoing phase III studies investigating this combination in the definitive setting will likely be informative. Currently, PACIFIC-4 (NCT03833154) and SWOG/NRG S1914 (NCT04214262), both of which randomize patients with early-stage NSCLC with high-risk features to treatment with SBRT with or without consolidative ICB, are currently enrolling (119,120). Notably, patients treated on the experimental arms of these studies receive radiation therapy with biologically effective doses (BEDs) in excess of 100 Gy in combination with ICB and as a result, the outcomes of these trials will likely provide additional valuable information on the safety of combining ablative doses of radiation with ICB.…”