2039 - Impact of Radiation Therapy on Long-Term Survival in Patients with KRAS-Mutant Stage IV NSCLC Treated with Immune Checkpoint Inhibitors

S. Fattahi¹, F. K. Keane², M. J. Khandekar³, J. Gainor⁴, and H. Willers⁵; ¹Harvard Radiation Oncology Program, Boston, MA, ²Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, ³Harvard Medical School, Boston, MA, ⁴Department of Medicine, Massachusetts General Hospital, Boston, MA, ⁵Massachusetts General Hospital, Boston, MA

Purpose/Objective(s): KRAS mutations are the most common oncogenic drivers in NSCLC. While the use of immune checkpoint inhibitors (ICI) has improved outcomes in many patients (pts), the importance of radiation therapy (RT) for long-term survival post-ICI remains unknown. Materials/

Methods: This single-institution cohort was part of the previously reported multi-institutional Stand Up To Cancer cohort of KRAS-mutant stage IV NSCLC pts treated with ICI (XXX, Cancer Discovery 2018). Primary progression free survival (pPFS) and overall survival (OS) were calculated from start of ICI. Secondary PFS (sPFS) was calculated from end of last RT course. Survival times were estimated using the Kaplan-Meier method. Patient, tumor, and treatment characteristics were extracted from the electronic health records. This study was approved by the IRB.
Results: Between 1/2015 and 11/2016, 39 stage IV NSCLC pts with known KRAS mutation were treated with ICI. 46.2% of pts were female and 97.4% had a smoking history. Median age at initial diagnosis was 63 years. KRAS co-mutations included TP53 (KP 25.6%), LKB1 (KL 15.4%), and both (KPL 5.1%). The most common ICI was nivolumab in 79.5% of pts. 82.1% received systemic therapy prior to start of ICI and 38.5% afterwards. Median number of lines of systemic therapies was 2 (range 1-8). 64.1% of pts received RT prior to ICI and 51.3% afterwards. In those who received RT after ICI, the median number of courses was 2 (range 1-6). With median follow-up of 79.2 months, median OS and 7-year OS were 28.6 months (range 0.9-109.8) and 22% (95% CI 9.9-37.1), respectively. Median pPFS and sPFS were 5.6 and 6.2 months, respectively. Receipt of any RT was associated with longer OS (p = 0.033). 11 pts survived > 5 years from start of ICI; 5 of them with no evidence of disease (NED) at last follow up and 2 still receiving a G12C inhibitor. In these patients, KRAS co-mutation status was KL n=0, KP n=4, and KPL n=1. 6 tumors were G12C. Median PD-L1 score was 35% (range 0-90). In 8 of these 11 long-term survivors (72.3%), definitive fractionated or stereotactic RT was employed at least once at any point during their post-ICI course to control isolated progression (lung/mediastinum n=7, brain n=5, abdominal n=2), with the latest RT for nodal recurrence 7.4 years after ICI. Strikingly, 1 pt who is NED at 8.7 years successfully received RT x 2 and taxane x 1 for hyperproliferative mediastinal oligoprogression.
Conclusion: In this small but unique cohort with maximum possible follow up since FDA approval of nivolumab in 2015, a significant number of pts experienced long-term OS post-ICI up to 9 years. ~72% of these pts received definitive RT up to 7.4 years after ICI suggesting that it played an important role in facilitating OS. Our findings have implications for surveillance and RT approaches in clinical practice and warrant additional studies in larger cohorts.