How Well Does Radiotherapy Pair With Dual PD-1/LAG-3 Blockade in NSCLC?

The TRIPL trial (NCT06865339) is testing thoracic radiotherapy combined with dual PD-1 and LAG-3 blockade, using cemiplimab (Libtayo) plus the investigational LAG-3 inhibitor fianlimab, in patients with locally advanced non-small cell lung cancer (NSCLC).¹ The trial builds on the SPRINT trial (NCT03523702), which combined radiotherapy with pembrolizumab (Keytruda) and produced a 1-year progression-free survival rate of 76%, though some patients still experienced disease recurrence.² Additionally, the regimen produced 1- and 2-year overall survival rates of 92% and 76%, respectively. Investigators concluded that pembrolizumab plus risk-adapted radiation may be a promising approach for patients with locally advanced NSCLC.

Nitin Ohri, MD, MS, a professor of radiation oncology at Montefiore Einstein Comprehensive Cancer Center in the Bronx, New York, spoke with CancerNetwork^® at the 2026 American Society for Radiation Oncology (ASTRO) Annual Meeting, as the TRIPL trial’s principal investigator, about the biological rationale for adding a second checkpoint target rather than simply intensifying PD-1 blockade alone. Based on previous data showing that using higher doses of the same drugs may not improve outcomes, Ohri noted that attacking the disease with 2 different checkpoint inhibitors may be a promising approach.

Transcript:

CancerNetwork: You’re studying thoracic radiotherapy combined with dual PD-1 and LAG-3 blockade. What’s the biological rationale for adding a second checkpoint target on top of radiotherapy, rather than simply intensifying PD-1 blockade alone?

Ohri: We had excellent outcomes combining PD-1 therapy with radiotherapy for locally advanced non-small cell lung cancer in SPRINT, but some patients unfortunately did still develop recurrence. We’re looking to improve outcomes further by adding a LAG-3 inhibitor, which has shown promise in several studies, including for skin cancers and lung cancer. PD-1 therapy is often effective, but studies have shown that using higher doses of the same drugs does not improve outcomes. Attacking from 2 different strategies with 2 different checkpoint inhibitors is the approach that we find most promising.

References

1. Thoracic radiotherapy and inhibition of PD-1 and LAG-3 for locally advanced non-small cell lung cancer (TRIPL). ClinicalTrials.gov. Updated April 13, 2026. Accessed September 30, 2026. https://tinyurl.com/4jabftpt
2. Ohri N, Jolly S, Cooper BT, Kabarriti R, et al. Selective personalized radioImmunotherapy for locally advanced non-small-cell lung cancer trial (SPRINT). J Clin Oncol. 2024;42(5):562-570. doi:10.1200/JCO.23.00627