Personalizing Lung Cancer Treatment Reduces Toxicity and Improves Cure Rates

Nitin Ohri, MD, MS

Non–small cell lung cancer (NSCLC) causes approximately 2 million deaths each year worldwide.¹ Approximately one-third of patients initially present with locally advanced disease, meaning that the cancer is bulky and/or involves regional lymph nodes but has not spread to distant locations.²

A standard treatment for patients with locally advanced NSCLC consists of a 6-week course of daily thoracic radiotherapy along with concurrent radiosensitizing chemotherapy, often followed by adjuvant immunotherapy.³ With respect to radiotherapy dosing, systemic agents used, and treatment sequencing, patients are currently treated with a one-size-fits-all approach. Some patients may experience severe adverse effects (AEs) during or after chemoradiotherapy, including esophagitis, lung inflammation, and immuno- suppression.⁴ Many patients never reach the adjuvant immunotherapy phase because they experience severe AEs from chemoradiotherapy. In addition, immunosuppression resulting from chemoradiotherapy may render immunotherapy ineffective. Five-year survival rates remain below 50% for this patient population.³

New lung cancer treatment options have emerged in recent years, and several groups are exploring personalized treatment strategies that omit chemotherapy for some patients with locally advanced NSCLC. Chemotherapy-free lung cancer treatment would be especially helpful for patients who are frail or older, or who have biopsy findings that suggest that immunotherapy would be effective.

Advancing Personalized Lung Cancer Treatment

Chemotherapy can cause significant toxicity and is not always effective in preventing disease spread. Establishing chemotherapy-free treatment approaches for locally advanced NSCLC using biomarker testing to identify patients who could be treated effectively without chemotherapy would represent a major advance.

The phase 2 SPRINT trial (NCT03523702) was recently completed at Montefiore Einstein Comprehensive Cancer Center (MECCC), an National Cancer Institute–designated Comprehensive Cancer Center, Bronx, New York. Investigators evaluated patients with locally advanced NSCLC with high expression of PD-L1, which is a predictor of immunotherapy efficacy.⁴

Figure. Kaplan-Meier Curve for Overall Survival in Phase 2 SPRINT Trial²

Unlike many other studies testing chemotherapy-free treatment for locally advanced NSCLC, the SPRINT trial enrolled patients who were fit enough to receive standard chemotherapy and radiotherapy.⁵ Additionally, SPRINT participants received induction immunotherapy before radiotherapy to shrink their tumors and ensure they received immunotherapy, as most patients following the existing protocol do not make it to that phase of treatment. SPRINT participants then received 3 cycles of induction pembrolizumab (Keytruda); a 4-week course of personalized radiotherapy, often with lower doses; and additional pembrolizumab. SPRINT’s personalized radiotherapy strategy, which was piloted at MECCC to minimize the risk of treatment toxicity and risk of acute and delayed AEs (including immunosuppression) without compromising disease control, was another novel aspect of SPRINT that took treatment personalization to a new level.⁶

Few serious AEs related to study therapy occurred, and approximately 50% of treated patients (n = 25) had significant disease shrinkage after induction immunotherapy. Progression-free survival and overall survival rates exceeded expectations for this patient population, and disease improvement after induction immunotherapy was identified as a powerful predictor of long-term treatment efficacy (Figure).⁵ This finding indicates that measuring responses to induction therapy could help researchers quickly determine which novel immunotherapy agents should be tested in large trials for the management of locally advanced NSCLC to improve patient outcomes.

Future Immunotherapy and Chemotherapy-Free Studies

Clinical trials offer patients with locally advanced NSCLC access to novel treatments, along with the support of their respective health care team.

Building on the SPRINT findings, MECCC investigators are leading the multi-institutional phase 2 TRIPL (NCT06865339) and SPRINT2 trials in 2025, testing combinations of promising novel immunotherapy drugs targeting LAG3, NKG2A, and CD73, and more established drugs targeting PD-1/PD-L1. Both trials will incorporate induction dual-agent immunotherapy, which will be followed by personalized radiotherapy and then additional immunotherapy. Favorable results from these trials would support subsequent pivotal phase 3 trials looking to establish new treatment options for patients with locally advanced NSCLC.

In addition to these clinical trials, other treatment approaches being taken by MECCC investigators include the use of proton beam radiotherapy as well as primary tumor stereotactic body radiotherapy, the latter of which is being tested in the phase 3 NRG-LU008 trial (NCT05624996), with the overarching goal of improving cure rates and reducing treatment toxicity.⁷

Nitin Ohri, MD, MS, is a professor of radiation oncology at Montefiore Einstein Comprehensive Cancer Center in Bronx, New York.

References

1. Li C, Lei S, Ding L, et al. Global burden and trends of lung cancer incidence and mortality. Chin Med J (Engl). 2023;136(13):1583- 1590. doi:10.1097/CM9.0000000000002529
2. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377(20):1919-1929. doi:10.1056/NEJMoa1709937
3. Spigel DR, Faivre-Finn C, Gray JE, et al. Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. J Clin Oncol. 2022;40(12):1301-1311. doi:10.1200/JCO.21.01308
4. Bradley JD, Hu C, Komaki RR, et al. Long-term results of NRG oncology RTOG 0617: standard-versus high-dose chemoradiotherapy with or without cetuximab for unresectable stage III non-small-cell lung cancer. J Clin Oncol. 2020;38(7):706- 714. doi:10.1200/JCO.19.01162
5. Ohri N, Jolly S, Cooper BT, 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
6. Ohri N, Bodner WR, Kabarriti R, et al. Positron emission tomography-adjusted intensity modulated radiation therapy for locally advanced non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2018;102(4):709-715. doi:10.1016/j.ijrobp.2017.10.032
7. Giaddui T, Chen W, Yu J, et al. Establishing the feasibility of the dosimetric compliance criteria of RTOG 1308: phase III randomized trial comparing overall survival after photon versus proton radiochemotherapy for inoperable stage II-IIIB NSCLC. Radiat Oncol. 2015;11:66. doi:10.1186/s13014-016-0640-8