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Clinical Trial
. 2024 Apr 1;118(5):1481-1489.
doi: 10.1016/j.ijrobp.2023.11.040. Epub 2023 Dec 8.

Combining Dual Checkpoint Immunotherapy with Ablative Radiation to All Sites of Oligometastatic Non-Small Cell Lung Cancer: Toxicity and Efficacy Results of a Phase 1b Trial

Michael F Bassetti  1 , Brett A Morris  2 , Nan Sethakorn  3 , Joshua M Lang  4 , Jennifer L Schehr  5 , Shuang George Zhao  1 , Zachary S Morris  1 , Darya Buehler  6 , Jens C Eickhoff  7 , Paul M Harari  1 , Anne M Traynor  4 , Toby C Campbell  4 , Andrew M Baschnagel  1 , Ticiana A Leal  8
Affiliations
Clinical Trial

Combining Dual Checkpoint Immunotherapy with Ablative Radiation to All Sites of Oligometastatic Non-Small Cell Lung Cancer: Toxicity and Efficacy Results of a Phase 1b Trial

Michael F Bassetti et al. Int J Radiat Oncol Biol Phys. .

Abstract

Purpose: Ablative local treatment of all radiographically detected metastatic sites in patients with oligometastatic non-small cell lung cancer (NSCLC) increases progression-free survival (PFS) and overall survival (OS). Prior studies demonstrated the safety of combining stereotactic body radiation therapy (SBRT) with single-agent immunotherapy. We investigated the safety of combining SBRT to all metastatic tumor sites with dual checkpoint, anticytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4), and anti-programmed cell death ligand 1 (anti-PD-L1) immunotherapy for patients with oligometastatic NSCLC.

Methods and materials: We conducted a phase 1b clinical trial in patients with oligometastatic NSCLC with up to 6 sites of extracranial metastatic disease. All sites of disease were treated with SBRT to a dose of 30 to 50 Gy in 5 fractions. Dual checkpoint immunotherapy was started 7 days after completion of radiation using anti-CTLA-4 (tremelimumab) and anti-PD-L1 (durvalumab) immunotherapy for a total of 4 cycles followed by durvalumab alone until progression or toxicity.

Results: Of the 17 patients enrolled in this study, 15 patients received at least 1 dose of combination immunotherapy per protocol. The study was closed early (17 of planned 21 patients) due to slow accrual during the COVID-19 pandemic. Grade 3+ treatment-related adverse events were observed in 6 patients (40%), of which only one was possibly related to the addition of SBRT to immunotherapy. Median PFS was 42 months and median OS has not yet been reached.

Conclusions: Delivering ablative SBRT to all sites of metastatic disease in combination with dual checkpoint immunotherapy did not result in excessive rates of toxicity compared with historical studies of dual checkpoint immunotherapy alone. Although the study was not powered for treatment efficacy results, durable PFS and OS results suggest potential therapeutic benefit compared with immunotherapy or radiation alone in this patient population.

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Conflict of interest statement

This research was supported by the University of Wsiconsin Carbone Cancer Center Support Grant (Support Grant (P30 CA014520). All others acknowledge trial support from AstraZeneca to support this trial. TAL reports consulting fees from AstraZeneca, LilyUSA, Janssen Scientific, Daiichi Sankyo, and Merk Pharmaceuticals. JML reports consulting fees from AstraZeneca and Pfizer. TAL, JML, ZSM, PMH, SGZ reports research funding from NIH for various research projects unrelated to this project.

Figures

Figure 1:
Figure 1:
Progression free and overall survival analysis of all patients receiving at least one cycle of immunotherapy per protocol. A. Progression free survival is shown via Kaplan Meier analysis. Median PFS is 42 months. B. Overall survival shown via Kaplan Meier analysis. Median overall survival not yet met.
Figure 2:
Figure 2:
Progression free and overall survival analysis of patients with (n=4) or without (n=11) prior history of brain metastasis receiving at least one cycle of immunotherapy per protocol. A. Significantly longer PFS observed in patients without prior brain metastasis treated per protocol (42 vs 4 months, HR 6.1, p=0.0248). B. No significant difference observed between patients with or without prior brain metastasis treated per protocol (Median OS not reached for either group).
See this image and copyright information in PMC

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