Misty D. Shields, MD, PhD
Recent clinical trial data have reinforced the role of immunotherapy in the consolidative setting for patients with small cell lung cancer (SCLC) and non–small cell lung cancer (NSCLC), and ongoing research seeks to solidify the role of prophylactic cranial irradiation (PCI) in the modern era of extensive-stage SCLC (ES-SCLC) management, according to Misty D. Shields, MD, PhD.
“It’s exciting for our patients [that we can] identify novel targets that we can go after in the relapsed setting to help personalize care for patients with SCLC,” Shields said in an interview with OncLive®.
Shields is a translational medical oncologist at Indiana University (IU) Health; as well as an assistant professor of clinical medicine in the Department of Medicine in the Division of Hematology/Oncology at the IU School of Medicine and an associate member of Experimental and Developmental Therapeutics at the IU Melvin and Bren Simon Comprehensive Cancer Center in Indianapolis.
In the interview, Shields discussed the inefficacy of concurrent immunotherapy and chemoradiation in patients with SCLC and NSCLC, the ongoing debate surrounding the role of PCI in SCLC, and ongoing research at IU investigating longitudinal liquid biopsies to track tumor changes, identify therapeutic targets, and ultimately personalize treatment for patients with relapsed SCLC.
In particular, Shields noted how data from the phase 3 NRG-LU005 trial (NCT03811002) indicate that the addition of immuno-oncology (IO) to concurrent chemoradiotherapy provides no survival benefit in limited-stage SCLC (LS-SCLC). At the second planned interim analysis, at a median follow-up of 21 months, the 3-year overall survival rate was 44.7% (95% CI, 36.6%-52.4%) in the atezolizumab (Tecentriq) arm vs 50.3% (95% CI, 42.3%-57.8%) with chemoradiotherapy alone.1 She also highlighted the clinical implications of the phase 3 PACIFIC-2 trial (NCT03519971), which showed similar outcomes in patients with unresectable, stage III NSCLC. In PACIFIC-2, durvalumab (Imfinzi) administered concurrently with standard-of-care (SOC) chemoradiotherapy followed by consolidation durvalumab (n = 219) did not significantly improve progression-free survival outcomes vs placebo plus SOC chemoradiotherapy (n = 109; HR, 0.85; 95% CI, 0.65-1.12; P = .247).2
OncLive: What do recent findings from studies investigating IO plus concurrent chemoradiotherapy demonstrate about the efficacy of this approach compared with the use of consolidative therapy?
Shields: With immunotherapy [plus] concurrent chemoradiation, across the board, we’re not seeing a benefit in both LS-SCLC and early, locally advanced NSCLC. We believe lymphodepletion is occurring [via] the radiation to the thoracic area that may be depleting essential white blood cells that are needed to mount an immune response for durable responses for patients with both NSCLC and SCLC. The idea that has been consistent and proven in multiple studies, including PACIFIC-2 and NRG-LU005, is that immunotherapy should not be given with concurrent chemoradiation. [Instead, immunotherapy] should be considered afterward as consolidative [therapy], pending there’s no progression on imaging after the completion of concurrent chemoradiation.
What has been the evolution of the role of PCI in patients with ES-SCLC?
PCI is preventive radiation to the brain to help improve survival and outcomes, including in intracranial progression of metastases, which is a sanctuary site for patients who are diagnosed with SCLC. Historically, the Saltzman and cooperative groups have suggested that PCI was beneficial for patients with limited-stage and extensive-stage [disease]. Then, [in 2017], we saw the ex-United States phase 3 trial data [UMIN000001755] from [Toshiaki Takahashi, MD, PhD, of the Shizuoka Cancer Center in Nagaizumi, Japan, et al] showing that there is no benefit with PCI in extensive-stage [disease]. This called into question our dogma of how we treat patients with ES-SCLC who have had an excellent response to induction chemotherapy and radiation or chemoimmunotherapy. [Therefore, PCI has] fallen out of favor for extensive-stage disease.
The phase 3 MAVERICK study [NCT04155034], a cooperative group study, is investigating whether patients with limited- or extensive-stage disease benefit from PCI. When evaluating these data, you have to consider other confounding variables, like investigator’s choice of patients who might be more fit for therapy and may have better outcomes and survival [based on factors] outside their disease or the [disease] biology. [PCI] is not without potential burden, [such as] acute and late toxicities, including cognitive effects. You want to be cautious and [make decisions with the goal of improving] patients’ quality of life. [It is important to make] sure we have data from the modern era [showing the benefit of] MRIs for all patients at baseline compared with MRIs [conducted] every 3 months as a potential SOC.
What SCLC research is ongoing at the IU School of Medicine?
We have exciting research here at the IU School of Medicine, led by my team with the Shields lab and our translational group, investigating the role of longitudinal liquid biopsies for patients with SCLC. All-comers can be consented and collected upon at baseline. Any time they have imaging scans—every 6 weeks to every 3 months—we can collect 3 tubes or more of blood, [then look] for RNA expression, DNA for novel mutations, and methylation for which genes are on or off, as well as [conduct] proteomics to evaluate the proteins and subtypes.
This will help us see over time how patients’ tumors might be changing with therapies, including the novel therapies that patients are receiving that we don’t have much data on. We’ve collected and consented approximately 75 patients, and that number is continuing to increase. We’re seeing some of those novel data rolling out.
References
- NRG Oncology trial implies the addition of atezolizumab concurrently to standard of care does not improve survival in limited-stage small cell lung cancer. News release. NRG Oncology. September 30, 2024. Accessed September 4, 2025. https://www.nrgoncology.org/Home/News/Post/nrg-oncology-trial-implies-the-addition-of-atezolizumab-concurrently-to-standard-of-care-does-not-improve-survival-in-limited-stage-small-cell-lung-cancer
- Bradley JD, Sugawara S, Lee KHH, et al. Durvalumab in combination with chemoradiotherapy for patients with unresectable stage III NSCLC: final results from PACIFIC-2. ESMO Open. 2024;9(suppl 3):102986. doi:10.1016/j.esmoop.2024.102986