Combining SABR with Immunotherapy to Improve Outcomes in Early-Stage NSCLC

For individuals with an early-stage non-small-cell lung cancer (NSCLC), research combining prospective and propensity-matched data has shown that stereotactic ablative radiotherapy (SABR) can achieve similar overall survival to surgery, with fewer side effects.1 Although SABR attains more than 90% local control rates, most recurrences occur regionally or outside the thorax. To address this, there is growing interest in combining SABR with immunotherapy (immuno-SABR) for early-stage NSCLC. This combination has the potential to enhance the immune system’s response, potentially transforming tumors into specific targets for the immune system, thus improving treatment outcomes.

Immunotherapy has become a crucial treatment modality for stage III and stage IV non-small cell lung cancer (NSCLC). In stage III, combining immunotherapy with chemoradiotherapy has increased 5-year survival rates from 33.4% to 42.9%.4 In stage IV, immunotherapy has significantly improved 5-year survival rates—and is now standard of care—raising them from about 5% previously to 15-20%, substantially extending and enhancing the lives of patients with advanced NSCLC. Previous clinical studies have demonstrated the synergistic advantages of combining radiotherapy with immunotherapy, resulting in improved treatment outcomes and response rates across various cancer types, including metastatic disease.5,6

Radiotherapy induces immunogenic cell death and enhances the release of tumor-associated antigens, promoting a more robust anti-tumor immune response.7 High-dose radiotherapy increases tumor antigens, PD-L1 expression, and T-cell activation, effectively turning tumors into in situ vaccines, enhancing local destruction and micrometastatic control. Tumor-draining lymph nodes (TDLNs) play a pivotal role in initiating immune responses. Immune cells differentiate into progenitors in TDLNs and migrate to the TME, contributing to systemic immunity. Immuno-SABR has the potential to enhance this immune priming effect by promoting immune cell activation within TDLNs. The impact of SABR dose and fractionation on systemic immune responses varies in preclinical studies, with some suggesting a preference for single high-dose SABR, while others favoring low-dose SABR when combined with immunotherapy, in order to elicit favorable local and systemic responses. These findings provide a basis for integrating SABR and immunotherapy for early-stage NSCLC to reduce the risk of regional and distant metastasis.

Immuno-SABR also shows promise in overcoming challenges seen with immunotherapy alone, such as tumor resistance. Localized radiation from SABR can create a favorable tumor microenvironment (TME) that enhances tumor responsiveness to the immune system. Additionally, the use of adjuvant immune checkpoint inhibitors (ICI) was shown to enhance local tumor control in locally advanced NSCLC in the PACIFIC trial.2

To assess the benefits of immuno-SABR, Chang et al. conducted a phase 2 randomized trial,3 comparing SABR alone to SABR combined with nivolumab (I-SABR) for early-stage or isolated parenchymal recurrent node-negative NSCLC. This was the first completed randomized study to investigate the combination of immunotherapy and SABR in this population, and the primary endpoint was the 4-year event-free survival rate in treated patients.

The study found that combining SABR with a short course of nivolumab (4 courses) significantly improved event-free survival compared to SABR alone, resulting in a 77% versus 53% event-free survival rate at 4 years (p=0·0080). More than 80% of patients received a 4-fraction scheme of SABR and 20% of the study population comprised potentially operable patients. Immuno-SABR reduced the risk of recurrence, disease progression, or death by 62%, compared to SABR alone. These benefits extended to patients who were PD-L1 negative, and this may be attributed to SABR’s immune-stimulating effects. The immuno-SABR group also experienced lower rates of first relapse, reducing all types of recurrence from 36% to 12%, along with lower mortality.

The Chang et al. study also demonstrated a favorable safety profile for short-course nivolumab, with a low incidence of grade ≥2 pneumonitis, where only one case was reported in the SABR group compared to two cases in the nivo-SABR group. However, 15% of patients in the nivo-SABR group experienced grade 3 events, primarily fatigue, and immunotherapy was discontinued in 8% of patients.

The results shown by Chang et al3 indicate that short-course immunotherapy with SABR holds promise as a potential treatment approach for early-stage NSCLC patients. This sets an important precedent for ongoing phase 3 trials in this patient population, including:

• PACIFIC-4 (NCT03833154) with durvalumab or osimertinib for patients with an EGFR mutation;
• KEYNOTE-867 (NCT03924869) with pembrolizumab; and
• SWOG/NRG S1914 (NCT04214262) with atezolizumab.

It is important to note that the duration of ICI administration varies in these trials. Initially, PACIFIC-4 planned 2 years of adjuvant durvalumab after SABR but later switched to concurrent administration for 2 years. A separate cohort of patients with EGFR mutations in PACIFIC-4 will receive adjuvant osimertinib for 3 years. In contrast, KEYNOTE-867 combines SABR with a placebo or pembrolizumab for up to 1 year. SWOG/NRG S1914 uses SABR alone or in combination with neoadjuvant, concurrent, and adjuvant atezolizumab for 6 months.

The translational analyses of Chang et al.’s I-SABR study is eagerly awaited as identifying predictive biomarkers is crucial for evaluating combination therapy. Traditional markers such as PD-L1 expression and tumor mutation burden may not capture the dynamic changes in the tumor microenvironment and systemic immune responses.8 Recent research has focused on specific immune cell subsets, such as stem-like/progenitor-exhausted T cells in tumor-draining lymph nodes,9 and the kinetics of CD8-positive T cell subsets in peripheral immunity. Additionally, Ki67-positive, PD-L1-positive, and CD8-positive T cells in peripheral blood may be indicative of tumor-specific T cells and correlate with positive clinical outcomes.10 These immune subpopulations hold promise as dynamic biomarkers for monitoring responses in combination therapy. Furthermore, Voong et al. reported a gradual and temporary activation of antitumor neoantigen-specific T-cell responses following SABR alone. This suggests that systemic immune responses are triggered after SABR for small-volume early-stage NSCLC; insights valuable for determining the optimal timing for ICI administration in conjunction with SABR.11

Toxicity risks associated with the integration of immunotherapy and SABR remains a cause for concern. For example, Wu et al. reported a 16.7% incidence of grade ≥3 pulmonary toxicities when combining durvalumab (1500 mg every 4 weeks) with SABR in early-stage NSCLC patients.12 However, other studies have not raised significant concerns. For instance, a 20-patient study evaluating atezolizumab in medically inoperable NSCLC showed good tolerance to the treatment.13 Likewise, Altorki et al. did not identify a significant occurrence of pneumonitis as adverse events in their study where durvalumab was combined with SABR in potentially resectable early-stage NSCLC patients (clinical stages I-IIIA).14 However, it is worth noting that Altorki et al. administered a lower durvalumab dose (1.12 g every 3 weeks) and included patients with more advanced-stage NSCLC, which could affect immune responses and the likelihood of adverse events. The absence of pneumonitis might also be attributed to resection of irradiated lung tissue.

Achieving an optimal balance in the delivery of radiation and immunotherapy, while effectively managing potential side effects is an evolving area of interest in the field of immunotherapy in combination with SABR. Substantial clinical and translational research is essential to establish the true effectiveness and optimal utilization of this treatment approach.

References

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