SBRT Shines in Early-Stage NSCLC and Demonstrates Efficacy With Immunotherapy

Stereotactic ablative radiotherapy (SABR) has shown benefit in early-stage non–small cell lung cancer (NSCLC) and has also shown clinical benefit in combination with immunotherapy, making it a viable treatment option to consider, according to a presentation given by Joe Y. Chang, MD, PhD, during The Radiation Oncology Summit: ACRO 2024. Chang explained that immunotherapy plus SABR could be evaluated as a curative approach.¹

A phase 2 study (NCT03110978) found that the addition of immunotherapy to SABR significantly improved event-free survival (EFS) at 4 years in patients with early-stage, treatment-naive or lung parenchymal recurrent node-negative NSCLC. Rates were 53% (95% CI 42%-67%) in the SABR alone arm vs 77% (95% CI, 66%-91%) with SABR plus nivolumab ([Opdivo] HR, 0.42; 95% CI, 0.22-0.80; P = .0080), and all subgroups examined experienced benefit with the combination. Patients who were randomly assigned in the trial received SABR (n = 78) of 50 Gy in 4 fractions or 70 Gy in 10 fractions vs immunotherapy plus SABR (n = 78) with 4 doses of 480 mg nivolumab given in combination with the same SABR dose.²

“For local recurrence, rates dropped from 13.3% to 0%, [for regional] from 10.7% to 6.1%, distinct [recurrence] from 16.0% to 3.0%, and deaths from 12.0% to 6.1%,” Chang explained on the addition of immunotherapy to SABR vs SABR alone.¹ Regarding toxicities, there were no grade 3 or higher adverse effects (AEs) associated with SABR.²

“Immunotherapy [plus] SABR significantly improved EFS at 4-years in early-stage NSCLC with tolerable toxicity and should be considered as a treatment option. Optimizing immunotherapy with radiation therapy is crucial with appropriate indications, timing, duration, [and] radiotherapy regimens in localized NSCLC,” Chang, the director of Stereotactic Ablative Radiotherapy, a thoracic radiation oncologist, and recipient of the tenured Texas 4000 Distinguished Professorship at The University of Texas MD Anderson Cancer Center in Houston, said in the presentation.

Adding Immunotherapy to SABR?

Chang added that ongoing randomized clinical trials are looking at the unresolved issues around induction and concurrent treatment. The phase 3 PACIFIC (NCT02125461) and PACIFIC-2 (NCT03519971) studies have shown that timing of immunotherapy is crucial. He noted that concurrent chemotherapy and radiation therapy of 60 Gy in 30 fractions plus durvalumab (Imfinzi) failed to improve progression-free survival (PFS) in the PACIFIC-2 trial.¹

Evolving approaches with immune checkpoint inhibitors such as pembrolizumab (Keytruda) and durvalumab are examining neoadjuvant vs adjuvant vs perioperative combination approaches with radiation therapy. The addition of pembrolizumab to radiotherapy significantly increased responses in patients with metastatic NSCLC in a pooled analysis of the phase 2 PEMBRO-RT trial (NCT02492568) and phase 1/2 MDACC trial (NCT02444741). The median overall survival (OS) was 8.7 months (IQR, 6.4-11.0) for those who received the immunotherapy alone (n = 76) compared with 19.2 months (IQR, 14.6-23.8) for patients treated with the combination (n = 72; (HR, 0.67; 95% CI, 0.54-0.84; P =.0004). In PEMBRO-RT, pembrolizumab was given sequentially less than 1 week after the last dose of radiotherapy of 24 Gy in 3 fractions; a radiotherapy dose of 50 Gy in 4 fractions or 45 Gy in 15 fractions was given concurrently with pembrolizumab in the MDACC trial.³

Chang noted questions remain on whether patients who achieve a pathologic complete response still need surgery and he added that “not all radiotherapy is created equal”—there are local and systemic effects.¹

He added that a “personalized radiomic/biomarker AI model–guided immunotherapy [plus] SABR is needed in [the] future.”

SABR Proves Effective Alone in Early-Stage NSCLC

A propensity-matched prospectively collected cohort analysis of the International Early Lung Cancer Action Program (I-ELCAP) and the Initiative for Early Lung Cancer Research on Treatment (IELCART) in early-stage NSCLC revealed that regarding OS at 10 years, there was no difference with matched patients who received surgery (n = 1003) vs SBRT (n = 112; P = .74). Investigators noted these data support SBRT as an alternative treatment to surgery for patients with small, early NSCLC. Moreover, the cancer-specific survival rate was not significantly different between arms, at 90% (95% CI, 87%-92%) with surgery vs 88% (95% CI, 77%-99%) with SBRT at 10 years (P = .55).⁴

When examining surgery vs SABR in stage I NSCLC, Chang noted that “surgical risk defines options for stage 1 [and] individualized multidisciplinary management is crucial and required.” For patients with stage I medically operable disease lobectomy is the clear choice and when disease is borderline operable, sublobar surgery vs SABR becomes the preferred option, according to Chang. He added that when disease is medically inoperable, SABR should be used. Considerations for surgery vs SABR include age, Karnofsky Performance Scale/comorbidity, heart function, and tumor size and location.¹

Data from a phase 2 trial (NCT00489008) examining SABR in patients with stage I NSCLC (n = 65) found that the 7-year estimated cumulative incidence of local recurrence was 8.1% (95% CI, 3.5%-18.8%) and any recurrence rate was 30.9% (95% CI, 20.7%-46.0%).⁵

Chang also noted that the phase 3 VALOR study (NCT02984761) opened in 2017 and has enrolled 280 of 670 patients with operable early-stage NSCLC to receive lung cancer surgery vs stereotactic radiotherapy; the study is currently enrolling patients.¹

References

1. Chang, JY. Exploring stereotactic ablative radiotherapy and immunotherapy in NSCLC. Presented at: 2024 ACRO Annual Meeting; March 13-16, 2024; Orlando, FL.
2. Chang JY, Lin SH, Dong W, et al. Stereotactic ablative radiotherapy with or without immunotherapy for early-stage or isolated lung parenchymal recurrent node-negative non-small-cell lung cancer: an open-label, randomised, phase 2 trial. Lancet. 2023;402(10405):871-881. doi:10.1016/S0140-6736(23)01384-3
3. Theelen WSME, Chen D, Verma V, et al. Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Respir Med. 2021;9(5):467-475. doi:10.1016/S2213-2600(20)30391-X
4. Henschke CI, Yip R, Sun Q, et al; I-ELCAP; IELCART Investigators. Prospective cohort study to compare long-term lung cancer-specific and all-cause survival of clinical early stage (T1a-b; ≤20 mm) NSCLC treated by stereotactic body radiation therapy and surgery. J Thorac Oncol. 2024;19(3):476-490. doi:10.1016/j.jtho.2023.10.002
5. Sun B, Brooks ED, Komaki RU, et al. 7-year follow-up after stereotactic ablative radiotherapy for patients with stage I non-small cell lung cancer: results of a phase 2 clinical trial. Cancer. 2017;123(16):3031-3039. doi:10.1002/cncr.30693