Trial no. NCT04821778 registered in ClinicalTrials.gov.

The annual ImmunoRad Conference has established itself as a recurrent occasion to explore the possibility of combining radiation therapy (RT) and immunotherapy (IT) for clinical cancer management. Bringing together a number of preclinical and clinical leaders in the fields of radiation oncology, immuno-oncology and IT, this annual event fosters indeed essential conversations and fruitful exchanges on how to address existing challenges to expand the therapeutic value of RT-IT combinations. The 8th edition of the ImmunoRad Conference, which has been held in October 2024 at the Weill Cornell Medical College of New York City, highlighted exciting preclinical and clinical advances at the interface between RT and IT, setting the stage for extra progress toward extended benefits for patients with an increasing variety of tumor types. Here, we critically summarize the lines of investigation that have been discussed at the occasion of the 8th Annual ImmunoRad Conference.

Several FDA-approved anti-PD-L1 (programmed cell death ligand-1) monoclonal antibodies (mAbs) are used to treat cancer. While these mAbs primarily target and intercept PD-L1:PD-1 inhibitory signaling in T-cells, the Fc-domains of these mAbs are distinct, and the unique cellular cascades triggered by differing Fc-domains of PD-L1 mAbs have not been directly investigated. In this study, we compared the innate immune effects of two widely used anti-PD-L1 IgG1 mAbs which bear distinct Fc-domains, avelumab (native-Fc) and durvalumab (mutated-Fc), using two-cell and three-cell co-culture systems containing Natural Killer cells (NK-cells), dendritic cells (DCs) and various tumor cell lines of multiple cancer origins. We show a robust enhancement in NK-cell effector function, DC maturation, reciprocal NK:DC crosstalk and DC editing that is unique to avelumab treatment using multiple functional immune assays. By transcriptomic analysis, we show for the first time pivotal differences in gene sets involved in NK-cell effector function, DC maturation, immunoregulatory interactions, and cytokine production between innate immune cells treated with avelumab versus durvalumab. Furthermore, we report several previously unknown Fc-receptor-associated biological pathways uniquely triggered by avelumab. Our findings elucidate novel mechanisms of Fc-dependent actions of PD-L1 mAbs which may inform their use in future clinical trials.

To evaluate the efficacy and safety of induction immunochemotherapy followed by hypo-fractionated radiotherapy (Hypo-RT) for locally advanced unresectable non-small cell lung cancer (LA-NSCLC).

This retrospective analysis involved the data of 35 patients with unresectable stage III LA-NSCLC receiving immunotherapy plus Hypo-RT from January 1, 2019, to December 31, 2023. At least 2 cycles of induction immunochemotherapy were initially administered, followed by a definitive Hypo-RT at 4 Gy per fraction. The primary endpoint was overall survival (OS) and the secondary endpoints were progression-free survival (PFS) and grade ≥ 3 nonhematologic toxicities. Time-to-event outcomes for the entire cohort were calculated using the Kaplan-Meier method.

At a median follow-up of 31.5 months (95% confidence interval, 26.1 to 36.9 months), median OS did not reach, with 1, 2, and 3-year OS rates of 100.0%, 82.5%, and 77.3%, respectively. Disease progression or death was recorded in 18 (51.4%) patients, with a median PFS of 28.0 months (95% CI, 9.4 to 46.6 months). The 1, 2, and 3-year PFS rates were 74.3%, 55.7%, and 47.6%, respectively.

Induction immunochemotherapy followed by Hypo-RT demonstrated promising efficacy and acceptable toxicity in patients with LA-NSCLC. Studies on Hypo-RT combined with induction and consolidation immunotherapies are warranted in the future.

Standard radiation therapy (RT) for locally advanced nonsmall cell lung cancer (LA-NSCLC) employs a uniform dose of approximately 60 Gy. Recent trials demonstrated that RT dose escalation may not improve outcomes and may cause added toxicity. We previously performed a single-arm trial testing a personalized, risk-adapted, and deintensified RT strategy. We now report findings from a randomized trial testing this novel approach.

Patients with LA-NSCLC with Eastern Cooperative Oncology Group performance status 0-2 were eligible for this trial. Metabolic tumor volume for each pulmonary tumor and involved lymph node was calculated using fludeoxyglucose PET. Participants were randomly assigned 1:1 to receive standard RT (60 Gy in 30 fractions delivered to pulmonary tumors and involved lymph nodes) versus dose-painted RT (55 Gy delivered to tumors and lymph nodes with metabolic volume exceeding 20 cm3 and 44-48 Gy to other lesions, all in 20 fractions). Concurrent chemotherapy and standard adjuvant therapy were given in both arms. The primary objective was to characterize patient-reported outcomes using Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events. Secondary objectives included comparing outcomes between study arms.

Fifty patients were enrolled. The most common grade 3 patient-reported adverse events within 90 days of RT completion were dysphagia (38%), fatigue (38%), cough (32%), and wheezing (28%). The median progression-free survival duration is 18 months, and the median overall survival duration is 42 months. Progression-free survival and overall survival rates are similar across study arms (logrank P = .562 and .765, respectively). There have been 3 cases of in-field disease progression, with 1 in the control arm and 2 in the dose-painted arm. Grade 3-4 lymphopenia was reduced with dose-painted RT (48% vs 81%, chi-square P = .012).

High-grade patient-reported toxicity in patients with LA-NSCLC who are treated with concurrent chemoradiotherapy is common. We found no evidence that risk-adapted RT de-escalation compromises clinical outcomes. Follow-up studies testing the ability of this approach to improve the safety profile of chemoradiotherapy are warranted.

We investigated the efficacy and toxicity of thoracic radiation therapy (RT) plus concurrent and consolidation carboplatin with either solvent-based paclitaxel (sb-paclitaxel) or solvent-free nanoparticle albumin-bound paclitaxel (nab-paclitaxel).

This multicenter phase 1/2 randomized trial included patients with inoperable stage IIIA/B nonsmall cell lung cancer (AJCC 7) and an Eastern Cooperative Oncology Group performance status of 0-1. In phase 1, 6 patients received weekly nab-paclitaxel (50 mg/m²) and carboplatin (AUC 2) with concurrent thoracic RT (60 Gy in 30 fractions), followed by nab-paclitaxel (100 mg/m²) on days 1, 8, and 15 and carboplatin (AUC 6) on day 1 for two 21-day cycles. In phase 2, 92 patients were randomly assigned to weekly sb-paclitaxel (50 mg/m²) or nab-paclitaxel (40 mg/m²) with concurrent RT, followed by consolidation therapy with sb-paclitaxel or nab-paclitaxel and carboplatin for 2 cycles.

Two phase 1 patients had dose-limiting toxicities, setting the phase 2 nab-paclitaxel dose at 40 mg/m². For the phase 2 cohort, 2-year overall survival was 67% for sb-paclitaxel and 56% for nab-paclitaxel (P = .10), with progression-free survival of 44% and 27%, respectively (P = .14). Fewer patients completed consolidation with nab-paclitaxel (26%) versus sb-paclitaxel (58%) (P = .005). Grade 3 and higher adverse events were more frequent with nab-paclitaxel (56%) than with sb-paclitaxel (30%) (P = .029).

Nab-paclitaxel was associated with higher toxicity and numerically lower efficacy than sb-paclitaxel when used with thoracic radiation in locally advanced nonsmall cell lung cancer.

Chemoradiotherapy (CRT) followed by durvalumab is the standard of care for unresectable locally advanced NSCLC. Limited prospective data have been reported on intensity-modulated radiotherapy (IMRT)-adapted CRT in the immunotherapy era.

In this multicenter prospective observational study, patients underwent IMRT-adapted CRT (platinum-doublet chemotherapy plus 60 Gy IMRT in 30 fractions under a prespecified radiation protocol), followed by consolidative durvalumab. The primary outcome was the durvalumab introduction rate within 42 days post-CRT.

Thirty-two patients with unresectable locally advanced NSCLC were enrolled between November 2019 and February 2021. Among the 28 evaluable cases, durvalumab was introduced in 24 (85.7%, 90% confidence interval: 70.2%-95.0%) of 28 patients after CRT, achieving the primary end point. All 29 patients who received IMRT completed the scheduled 60 Gy radiotherapy dose. One year of durvalumab treatment was completed in 12 of 24 patients (50%). In the 24 patients who were durvalumab-introduced, the median progression-free survival and overall survival were 20.9 (95% confidence interval: 6.9-not evaluable) months and not reached, respectively. Two-year progression-free survival and overall survival rates were 44% and 73%, respectively. Among the 29 patients in the safety analysis set, there were no treatment-related deaths or grade 4 nonhematological adverse events. Pneumonitis grade 1 was observed in 13 patients (45%), grade 2 in seven (24%), and grade 3 in one (3%).

High durvalumab introduction rate was reported after the completion of IMRT-adapted CRT under a prespecified radiation protocol. Its efficacy has been suggested, with favorable safety profiles, including a low incidence of severe pneumonitis.

University Hospital Medical Information Network database ID: UMIN000038366.

Molecular testing plays a critical role in guiding optimal treatment decisions for lung cancer patients across a variety of clinical settings. While guidelines for biomarker testing exist in other jurisdictions, to date no best practice guidelines have been developed for the Australian setting. To address this need, the Royal College of Pathologists of Australasia collaborated with the Thoracic Oncology Group of Australasia to identify state-based pathologists, oncologists and consumer representatives to develop consensus best practice recommendations. Sixteen recommendations were established encompassing appropriate biomarkers, lung cancer subtype, tumour stage, specimen types, assay selection and quality assurance protocols that can inform and standardise best practice in molecular testing of lung cancer. These multidisciplinary evidence-based recommendations are designed to standardise and enhance molecular testing practices for lung cancers and should help ensure laboratories provide high-quality molecular testing of lung cancer for all Australians, including those from regional or remote communities.

Background/Objectives: The current staging of non-small cell lung cancer (NSCLC) relies on conventional imaging, which lacks the sensitivity to detect micrometastatic disease. The functional assessment of NSCLC progression may provide independent information to enhance the prediction of metastatic risk. The objective of this study was to determine if we could identify a metabolomic signature predictive of metastasis in patients with NSCLC treated with definitive radiation. Methods: Plasma samples were collected prospectively from patients enrolled in a clinical trial with non-metastatic NSCLC treated with definitive radiation. Metabolites were extracted, and mass spectrometry-based analysis was performed using a flow injection electrospray (FIE)-Fourier transform ion cyclotron resonance (FTICR) mass spectrometry (MS) method. Early metastasis was defined as metastasis within 1 year of radiation treatment. Results: The study cohort included 28 patients. FIE-FITCR produced highly reproducible profiles in technical replicates. A total of 51 metabolic features were identified to be different in patients with early metastasis compared to patients without early metastasis (all adjusted p-values < 0.05, Welch's t-test), including glycerophospholipids, sphingolipids, and fatty acyls. In the follow-up samples collected after the initiation of chemotherapy and radiation treatment, a total of 174 metabolic features were significantly altered in patients who developed early metastasis compared to those who did not. Conclusions: We identified several distinct changes in the metabolic profiles of patients with NSCLC who developed metastatic disease within 1 year of definitive radiation. These findings highlight the potential of metabolomic profiling as a predictive tool for assessing metastatic risk in NSCLC.

Chemoradiotherapy (CRT) followed by durvalumab (CRT → durvalumab) is standard of care to treat patients with unresectable, stage III non-small cell lung cancer (NSCLC). The RELEVANCE study was designed to provide real-world effectiveness and safety data for CRT → durvalumab in Canadian settings.

RELEVANCE was a retrospective, observational, multicenter chart review that included adult patients with unresectable, stage III NSCLC treated with CRT alone or CRT → durvalumab at 5 Canadian cancer centers. Key outcomes included treatment patterns, adverse events of special interest (AESI), and overall survival (OS).

487 patients were included (144 CRT alone; 343 CRT → durvalumab). Median follow-up was 43.1 and 35.8 months for the CRT alone and CRT → durvalumab groups, respectively. The most frequently observed regimen included radiotherapy dose 54-66 Gy and radiosensitizing carboplatin. Median treatment duration was 1.5 months (CRT alone) and 13.4 months (CRT → durvalumab), and 47 % of patients completed a full course of durvalumab. Median OS and 3-year OS rate were 21.3 months and 32 % for CRT alone and 44.6 months and 56 % for CRT → durvalumab. Exploratory analysis by programmed cell death-ligand 1 (PD-L1) expression status of the CRT → durvalumab group noted 3-year OS rates of 69 %, 44 %, and 39 % in the PD-L1 ≥ 50 % (high), 1 %-49 % (intermediate), and < 1 % (negative) populations, respectively (32 %, 38 %, and 24 % for CRT alone, respectively). PD-L1 high expression was associated with lower risk of death vs. PD-L1 negative expression (P < 0.05). The most common AESI with CRT → durvalumab was pneumonitis. Median OS for patients who completed durvalumab was not reached and was 41.3 months among patients who discontinued durvalumab due to AEs.

Results validate the treatment benefit and safety of the PACIFIC regimen in real-world Canadian settings. Among patients who received CRT → durvalumab, there was a correlation between increasing PD-L1 status and improved OS; however, shorter OS was observed in patients discontinuing durvalumab early due to AEs.

Real-world Canadian RELEVANCE study validates effectiveness and safety of durvalumab in patients with unresectable, stage III NSCLC.

The results of subgroup analyses of clinical trials are important reference information when considering the generalizability of a study treatment, i.e., providing the best treatment for each individual patient. The results of subgroup analyses are often presented in publications, etc. as forest plots focusing on patient backgrounds. However, it is important to fully understand and grasp some of the issues involved in subgroup analyses and to interpret the results carefully to apply them in clinical practice. Although the literature includes some reports on how subgroup analyses should be evaluated and handled for the purpose of establishing medical practice guidelines, most of the papers have mainly evaluated the reliability of subgroup analyses from a statistical perspective; few of them have incorporated clinical importance in their evaluations. Therefore, in December 2019, we established a Subgroup Analysis Review Committee consisting of oncologists specializing in lung cancer treatment and statistical experts among the members of the Guidelines Review Committee of the Japanese Lung Cancer Association, with the aim of appropriately reflecting subgroup analysis in Japanese lung cancer practice guidelines. We developed a new evaluation strategy to incorporate clinical aspects as well as reliability assessment. Specifically, on the basis of a clinical and statistical review of the problems with subgroup analyses presented as clinical trial results, we developed criteria and procedures to ensure consistency and fairness in the citation of clinical guidelines.

Malignant pleural effusion (MPE) is a severe complication in lung cancer, characterized by an immunosuppressive tumor microenvironment (TME) and limited therapeutic options. This study investigates the role of IL-6 in regulating immune suppression and tumor progression in MPE and evaluates the efficacy of dual IL-6 and PD-L1 blockade.

IL-6 levels were measured in MPE and paired serum samples from lung cancer patients, and correlations with PD-L1 expression and clinical outcomes were analyzed using publicly available datasets. RNA sequencing and immune deconvolution were used to assess immune cell infiltration. CAFs and immune cell infiltration were further evaluated using flow cytometry, immunohistochemistry, and multiplex immunofluorescence. In vitro co-culture systems were employed to simulate the MPE microenvironment and explore IL-6 interactions with CAFs, as well as its regulatory effect on tumor cell PD-L1 expression.

IL-6 levels were significantly elevated in MPE compared to paired serum and correlated with higher PD-L1 expression and poor survival outcomes in lung cancer patients. In the MPE mouse model, combination therapy with IL-6 and PD-L1 blockade reduced MPE volume, tumor burden, and PD-L1 expression, while enhancing T cell infiltration and alleviating TME immunosuppression. IL-6 was found to drive a positive feedback loop with iCAFs, promoting an immunosuppressive environment. In vitro, IL-6 from the MPE upregulated tumor cell PD-L1 expression the IL-6/STAT3 pathway.

This study identifies IL-6 as a critical contributor of immune suppression and tumor progression in MPE. The combination of IL-6 and PD-L1 blockade effectively alleviated immunosuppression and reduced tumor burden, offering a potential therapeutic approach for MPE management.

The standard of care for unresectable locally advanced non-small cell lung cancer (LA-NSCLC) includes post-chemoradiotherapy durvalumab consolidation therapy. However, moderate symptomatic pneumonitis (Grade 2) constitutes a significant adverse event that frequently leads to treatment interruption and warrants careful consideration of re-administration. We evaluated the efficacy and safety of durvalumab re-administration after recovery from grade 2 pneumonitis.

This retrospective study included 208 patients with LA-NSCLC who received post-chemoradiotherapy durvalumab consolidation therapy at seven institutions between July 2018 and March 2022. Among them, 62 developed Grade 2 pneumonitis that led to treatment interruption and were stratified into the durvalumab re-administration (n = 33) and durvalumab non-re-administration (n = 29) groups. Survival outcomes were analyzed using the Cox proportional hazards model.

Participants in the durvalumab re-administration group had significantly longer progression-free survival (PFS; 32.0 months [95 % confidence interval (CI): 11.7-Not Available (NA)] vs. 5.3 months [95 % CI: 3.5-17.4], P = 0.003) and overall survival (OS; not reached [95 % CI: 29.0-NA] vs. 27.1 months [95 % CI: 12.1-NA], P = 0.012) than in the durvalumab non-re-administration group. Pneumonitis recurred in 30.3 % of the re-administration group, albeit without Grade ≥ 3 events. Multivariate analysis identified durvalumab re-administration as an independent predictor of improved survival, with hazard ratios of 0.31 (95 % CI: 0.15-0.65, P = 0.002) for PFS and 0.33 (95 % CI: 0.13-0.82, P = 0.017) for OS.

Durvalumab re-administration after grade 2 pneumonitis was associated with prolonged survival and a low recurrence rate of mild pneumonitis, which suggests that re-administration is a feasible, effective strategy with adequate monitoring.

Immunotherapy targeting the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway has achieved remarkable clinical success, but there is a shortage of effective approaches for screening suitable patients. Recently developed PD-L1 nanobody probes have limitations, including limited availability of radionuclides, short tumor retention times, and accumulation in non-target organs. To enhance tumor retention and improve tumor-to-normal tissue contrast, we herein report the synthesis and preclinical evaluation of two Al18F-labeled bivalent PD-L1 nanobody probes ([18F]TzTCO-BINb109 and [18F]RESCA-BINb109). Preliminary results indicated that [18F]TzTCO-BINb109 had a greater affinity for PD-L1 and better stability than [18F]RESCA-BINb109. Micro-PET/CT revealed that [18F]TzTCO-BINb109 uptake in A549-PDL1 tumors peaked at 240 min post-injection (3.19 ± 0.49 %ID/g) and demonstrated sustained retention without in vivo defluorination. In contrast, [18F]RESCA-BINb109 exhibited shorter tumor retention (at 60 and 240 min, 2.08 ± 0.22 and 1.37 ± 0.26 %ID/g, respectively) and significant defluorination in vivo. Ex vivo biodistribution studies revealed that the tumor uptake of [18F]TzTCO-BINb109 was consistent with the PET results, with the highest uptake by A549-PDL1 tumor cells (3.43 ± 0.94 %ID/g) compared with H1975 (0.93 ± 0.18 %ID/g) and A549 (0.68 ± 0.12 %ID/g) cells observed at 240 min post-injection. Compared with the previously reported monomeric PD-L1-targeting nanobody probe, [68Ga]NOTA-Nb109, [18F]TzTCO-BINb109 demonstrated enhanced tumor uptake, prolonged retention, and superior tumor-to-normal tissue contrast, contributing to higher imaging quality. These results confirmed that the bivalent PD-L1 nanobody radioligand, [18F]TzTCO-BINb109, was a promising diagnostic probe for PD-L1 detection, efficacy evaluation, and prescription optimization of immune checkpoint inhibitor therapies.

Stage III non-small cell lung cancer (NSCLC) is a heterogeneous group and identification of subgroups with differential treatment responses is crucial. Addition of durvalumab to concurrent chemoradiotherapy (cCRT) has previously been shown to improve survival outcomes. Meanwhile, subgroups harboring KRAS mutations have been shown to have worse prognosis. We investigated whether KRAS mutational status may affect survival outcomes after adjuvant durvalumab following cCRT in stage III NSCLC.

In this multi-center retrospective study, we present a real-world dataset of all stage III NSCLC patients treated with curative-intent cCRT with molecular assessment, between 2016 and 2021 in the Västra Götaland Region of western Sweden. The study period includes the standard practice prior to the introduction of durvalumab, enabling evaluation of the potential impact of immune checkpoint blockade (ICB). Primary study outcomes were overall survival (OS) and progression free survival (PFS).

We identified 145 patients who received cCRT with curative intent, and 32 % harbored an activating mutation in the KRAS gene (KRASMUT; n = 46). Compared to patients with wild-type KRAS (KRASWT; n = 99), KRASMUT had worse OS (p = 0.047) and PFS (p = 0.038). This finding persisted on multivariate analysis with OS (HR 1.703, 95 % CI 1.074-2.702, p = 0.024) and PFS (HR 1.628, 95 % CI 1.081-2.453, p = 0.020). Within the subgroup that received cCRT alone, KRASMUT patients (n = 35) exhibited worse OS (p = 0.036) and PFS (p = 0.037) compared with KRASWT (n = 35). However, among those who received additional durvalumab after cCRT (KRASWT; n = 99. KRASMUT; n = 11) there were no significant differences in OS (0.788) or PFS (0.855) between the groups.

KRAS mutations are a negative prognostic factor after cCRT in stage III NSCLC, and the addition of durvalumab ameliorates the negative impact of harboring this mutation.

Advanced esophageal squamous cell carcinoma (ESCC) patients had poor prognosis and few effective drugs based on the randomized controlled trials (RCTs). In such a circumstance, recent RCTs have shown the clinical efficacy of immune checkpoint inhibitors (ICIs) as first- or second-line treatment for advanced ESCC patients. Tislelizumab is one of the anti-Programmed-Death-1 (PD-1) antibodies; at first, tislelizumab monotherapy showed clinical efficacy as a second-line treatment for advanced ESCC patients based on the results of the RATIONALE-302 trial. Since then, tislelizumab plus doublet chemotherapy has shown superiority in overall survival compared to doublet chemotherapy for untreated advanced ESCC patients in the RATIONALE-306 trial. In this review, we share the overview of the development of tislelizumab and discuss the future perspectives on ICIs for advanced ESCC patients. In our opinion, tislelizumab plus doublet chemotherapy is one of the first-line standard treatments for advanced ESCC patients regardless of Programmed cell Death ligand 1 expression. Some other ICI-containing treatments showed clinical efficacy for untreated ESCC patients; we need further investigation to select these treatments appropriately.

Bladder preservation therapy in combination with atezolizumab and radiation therapy trial, which was a multicenter, open-label, single-arm phase 2 study, showed a promisingly high interim clinical complete response (cCR) rate of 84.4% (38/45). In the present study, we aimed to identify potential tissue biomarkers for achieving cCR using bladder preservation therapy in combination with atezolizumab and radiation therapy.

We used tumor tissue samples of the bladder and blood samples collected from patients at baseline to analyze the tumor immune microenvironment at baseline using an integrated approach of immunophenotyping, genomic, and tumor-infiltrating lymphocyte (TIL) profiling.

Immune phenotype analysis revealed that cCR rates of patients with the desert phenotype were as similarly high as patients with excluded/inflamed phenotypes (73.3% [11/15] vs 93.3% [14/15], P = .33) despite lower programmed death-ligand 1 expression levels in the desert phenotype. Genomic and TIL profiling then revealed that increased CD8+ and CD204+ TIL infiltration, high CD8:forkhead box protein P3 ratios in the stroma of the excluded/inflamed phenotypes, and gene alterations, such as CDK12, GNAS, NOTCH2, and AR1D1A, were associated with a high cCR rate (93.3%). Furthermore, the characteristics of these dual TILs, CD8-forkhead box protein P3 ratios, and gene alterations (especially FGFR3) bifurcated the desert phenotype into 2 subgroups with different cCR rates (100% [11/11] and 0% [0/4]).

These potential subgroups, defined by combined molecular subclass and immune phenotype, could lead to the identification of good responders to atezolizumab plus radiation therapy for invasive bladder cancer. However, given the small cohort size and limited number of tumor samples, these findings should be viewed as hypothesis-generating and require further validation in larger studies.

Immuno-oncology (IO) is one of the fastest growing therapeutic areas within oncology. IO agents work indirectly via the host's adaptive and innate immune system to recognize and eradicate tumor cells. Despite checkpoint inhibitors being only introduced to the market since 2011, they have become the second most approved product category. Current Food and Drug Administration (FDA)-approved classes of IO agents include: immune checkpoint inhibitors (ICIs), chimeric antigen receptor T-cell therapy (CAR-T), bi-specific T-cell engager (BiTE) antibody therapy, T-cell receptor (TCR) engineered T cell therapy, tumor-infiltrating lymphocyte (TIL) therapy, cytokine therapy, cancer vaccine therapy, and oncolytic virus therapy. Cancer immunotherapy has made progress in multiple cancer types including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and urothelial carcinoma; however, several cancers remain refractory to immunotherapy. Future directions of IO include exploration in the neoadjuvant/perioperative setting, combination strategies, and optimizing patient selection through improved biomarkers.

The PACIFIC trial established consolidation immunotherapy (IO) after concurrent chemoradiotherapy as the standard treatment for unresectable stage III non-small cell lung cancer (NSCLC) by improving survival. However, the optimal timing of IO remains debated. This study analyzes the survival benefits and risks of IO concurrent with radiotherapy (RT) versus IO following RT.

A systematic search of multiple databases identified studies comparing IO concurrent with RT and IO following RT in unresectable stage III NSCLC. Data on overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were analyzed using the "meta" package in R, along with a single-center cohort study.

The meta-analysis showed improved PFS with IO concurrent with RT, with significant differences at 1 year (69.5 % vs 57.6 %) and 1.5 years (56.3 % vs 45.7 %). OS was slightly better with IO following RT, with fewer severe AEs (≥grade 3: 52.6 % vs 37.2 %). A single-center cohort validated superior PFS for the concurrent group (HR = 2.039, 95 % CI: 1.014-4.322, P = 0.046). Shorter intervals between RT and IO were associated with better PFS in the following group (HR = 1.002, 95 % CI: 1.001-1.003, P = 0.002).

Concurrent IO with RT during chemoradiotherapy significantly improved PFS in unresectable stage III NSCLC, though OS did not benefit due to a higher incidence of severe AEs. Earlier IO initiation after RT was associated with better PFS. Our findings suggest the potential benefits of concurrent IO for selected patients.

Inconsistencies in identifying dose-limiting cardiovascular substructures for treating stage III non-small cell lung cancer (NSCLC) have hindered the implementation of cardiac sparing treatment planning guidelines. This study aims to address these inconsistencies by performing a multivariable survival analysis with overall survival as the endpoint using a large, multinational database, followed by external validation.

Clinical and dosimetric parameters from 1587 stage III NSCLC patients treated at five institutes were analyzed. The whole heart, four cardiac chambers, great vessels and their combinations were considered. The dataset was divided into a training set (four institutes) and a test set (one institute). The optimal parameter set was identified through cross-validation, and the resulting multivariable Cox regression model was externally validated using the test set. Adjusted hazard ratios (aHRs) for all cardiovascular parameters were evaluated.

The strongest associations were found for low Dx% parameters. However, their incremental contribution to model performance, compared to clinical and lung dosimetric parameters only, was low, with small effect sizes. Specifically, the cardiovascular parameter identified by parameter selection was Left Side D5% (aHR: 1.007 Gy-1, 95 % CI: 1.004 - 1.010 Gy-1, p < 0.0001), which provided a slight improvement in model concordance index of 0.0062 (95 % CI: 0.0000-0.0127) in the training set and 0.0037 (95 % CI: -0.0200-0.0280) in the test set.

Although significant associations between cardiovascular parameters and survival were found, their small effect sizes should be considered when prioritizing cardiac sparing in stage III NSCLC treatment.

Tumor metabolism plays a pivotal role in shaping immune responses within the tumor microenvironment influencing tumor progression, immune evasion, and the efficacy of cancer therapies. Radiotherapy has been shown to impact both tumor metabolism and immune modulation, often inducing immune activation through damage-associated molecular patterns and the STING pathway. In this study, we analyse the particular characteristics of the tumour metabolic microenvironment and its effect on the immune microenvironment. We also review the changes in the metabolic and immune microenvironment that are induced by radiotherapy, with a focus on metabolic sensitisation to the effects of radiotherapy. Our aim is to contribute to the development of research ideas in the field of radiotherapy metabolic-immunological studies.

Radiotherapy (RT) is a cornerstone of cancer treatment. Compared with conventional high-dose radiation, low-dose radiation (LDR) causes less damage to normal tissues while potentially modulating immune responses and inhibiting tumor growth. LDR stimulates both innate and adaptive immunity, enhancing the activity of natural killer cells, dendritic cells, and T cells. However, the mechanisms underlying the effects of LDR on the immune system remain unclear.

To explore the history, research hotspots, and emerging trends in immune response to LDR literature over the past two decades.

Publications on immune responses to LDR were retrieved from the Web of Science Core Collection. Bibliometric tools, including CiteSpace and HistCite, were used to identify historical features, active topics, and emerging trends in this field.

Analysis of 1244 publications over the past two decades revealed a significant surge in research on immune responses to LDR, particularly in the last decade. Key journals such as INR J Radiat Biol, Cancers, and Radiat Res published pivotal studies. Citation networks identified key studies by authors like Twyman-Saint Victor C (2015) and Vanpouille-Box C (2017). Keyword analysis revealed hotspots such as ipilimumab, stereotactic body RT, and targeted therapy, possibly identifying future research directions. Temporal variations in keyword clusters and alluvial flow maps illustrate the evolution of research themes over time.

This bibliometric analysis provides valuable insights into the evolution of studies on responses to LDR, highlights research trends, and identifies emerging areas for further investigation.

Long-term analysis of PACIFIC revealed the clinical benefit of chemoradiotherapy combined with Durvalumab for unresectable non-small-cell lung cancer (NSCLC) stage III. ALLSTAR is a prospective registry aimed at validating the PACIFIC regimen in daily practice in Austria.

Patients were eligible if they had pathologically confirmed unresectable NSCLC III with a curative treatment option. The endpoints for this analysis were overall survival (OS), updated local control (LC), and progression-free survival (PFS).

The 2- and 3-year LC rates in patients who received total radiation doses > 66 Gy were 80% and 75%, respectively, which were superior to the standard treatment (65% and 54%; p-value 0.085). This benefit was even more pronounced in Durvalumab patients with 2- and 3-year LC rates of 82% and 79% with >66 Gy (p-value 0.068). The 2- and 3-year OS with Durvalumab was 71% and 63%, respectively, compared to 58% and 44% without Durvalumab (HR 0.552; 95%-CI 0.347-0.881; p-value 0.011). Patients who were treated with Durvalumab also had a significantly longer 2- and 3-year PFS (56% and 48%) than those without (35% and 20%; HR 0.469; 95%-CI 0.312-0.707; p-value < 0.001). Pulmonary side effects were observed in 66/188 (35%) patients, with one case of grades 4 and 5 each. Oesophageal toxicity grade 1-3 occurred in 93/188 (49%) cases.

The updated ALLSTAR analysis demonstrated sustained benefit of Durvalumab for OS and PFS, as well as a possible long-term benefit of radiation dose escalation > 66 Gy on LC.

Approximately 25% of patients with non-small cell lung cancer (NSCLC) present with Stage III disease. The standard treatment for inoperable patients involves definitive chemoradiotherapy (CRT) followed by 12 months of maintenance durvalumab. However, the incidence of pneumonitis-an adverse effect of this regimen-affects a significant proportion of patients. This study aimed to identify predictors of pneumonitis in a large cohort of patients with unresectable Stage III NSCLC receiving CRT and durvalumab, with a focus on common medical comorbidities.

Using data from the Veterans Health Administration's Corporate Data Warehouse, we identified 1,524 patients who received the standard regimen between June 2017 and July 2023. Pneumonitis was assessed via ICD codes and severity determined using National Cancer Institute criteria. We analyzed associations between pneumonitis and various covariates including age, comorbidities, and medication use.

Our findings indicated a cumulative pneumonitis incidence of 14.5%, with 7.68% of cases classified as grade 3 or higher. Significant risk factors included advanced age, higher Charlson Comorbidity Index (CCI), prior pneumonia, diabetes, obesity, and antibiotic use, particularly cephalosporins and macrolides. Notably, severe chronic obstructive pulmonary disease (COPD) and uncontrolled diabetes were associated with an increased risk of pneumonitis. In contrast, prior tobacco use and better ECOG performance status (lower score) were protective.

These results highlight the complex interplay between comorbid conditions, medication, and pneumonitis risk in patients undergoing CRT and durvalumab therapy. Further research is needed to explore these relationships and potentially inform strategies to mitigate pneumonitis risk.

Australian subset of the multicentric PACIFIC-R study (NCT03798535) in patients with unresectable, stage III non-small cell lung cancer without progression following chemoradiotherapy, found a median progression-free survival of 22.4 months (95% confidence interval, 17.5 to 30.8) confirming clinical benefit of durvalumab consolidation post-chemoradiotherapy in the real-world setting.

The Phase 3 PACIFIC trial established post-chemoradiotherapy (CRT) durvalumab consolidation as standard treatment for patients with unresectable, stage III non-small cell lung cancer (NSCLC). We present the results from the Australian subset of the multicentric PACIFIC-R study (NCT03798535) assessing the effectiveness of durvalumab in the real-world setting.

Patients with unresectable, stage III NSCLC without progression following CRT, receiving at least 1 dose of durvalumab (10 mg/kg intravenously, every 2 weeks) through an early access program (EAP) between September 2017 and December 2019, were enrolled. Primary endpoints, progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier method.

AS OF FEBRUARY 7, 2022, 165 PATIENTS (MEDIAN AGE: 67.0 years) with a median follow-up of 34.7 months were enrolled. Most received last radiation ≥42 days before durvalumab initiation (126, 79.2%) at a dose of 54 to 60 Gy (141, 88.7%). Median PFS was 22.4 months (95% confidence interval [CI], 17.5 to 30.8). The 3-year PFS and OS rates were 38.9% (95% CI, 31.0 to 46.7) and 59.1% (95% CI, 51.2 to 66.2). Pneumonitis was the most frequent adverse events of special interest (27, 16.4%); which led to treatment discontinuation in 19 (11.5%) patients.

The real-world results from the Australian PACIFIC-R subset confirm translation of the clinical benefit of post-CRT durvalumab consolidation in the pivotal PACIFIC trial to the real-world setting, showing favorable survival outcomes, irrespective of delays in durvalumab initiation post-radiation.

Airway stents improve respiratory conditions and Eastern Cooperative Oncology Group Performance Status scores in cases of airway stenosis, as observed in patients with stage III non-small cell lung cancer (NSCLC) who experience prolonged survival after undergoing chemoradiotherapy followed by durvalumab treatment. Herein, we report three cases of severe airway stenosis due to stage III NSCLC in patients who underwent airway stenting and subsequent stent removal after chemoradiotherapy and durvalumab administration. The number of stents removed will likely increase in the future due to the high response rates to molecular drugs and immune checkpoint inhibitors.

Background/Objectives: Patients with stage III non-small cell lung cancer represent a very heterogeneous group of patients. In the past, the standard of care for patients with inoperable stage III non-small cell lung cancer was concurrent or sequential radical radiotherapy and chemotherapy. But the progression-free survival was 8 months, and the 5-year overall survival rate was less than 20%. After the results of the PACIFIC study, the standard of care for this group of patients is chemoradiotherapy with durvalumab as consolidation therapy. The aim of our study was to evaluate the efficacy of consolidation durvalumab in a real-world setting after sequential CRT. Methods: We included 24 patients with unresectable stage III non-small cell lung cancer who did not progress after sequential chemoradiotherapy and who received durvalumab consolidation. Results: Median progression-free survival was 16 months, 95% CI (0.5-31.5), and median overall survival was 20 months, 95% CI (13.4-26.6 months). The twelve-month progression-free survival and overall survival rate were 55.1% and 68%, respectively, and the 18-month progression-free survival and overall survival rates were 44.1% and 56.5%, respectively. Conclusions: Durvalumab introduced a new era in the treatment of patients with unresectable stage III non-small cell lung cancer with a significantly prolonged 5-year overall survival rate. Our study is one of the few that investigated the efficacy of durvalumab in a real-world setting after sequential CRT. Our results showed that durvalumab is effective in patients who were treated with sequential CRT. However, the time between radiotherapy termination and the start of durvalumab should be shorter.

Definitive thoracic reirradiation can improve outcomes for select patients with non-small cell lung cancer (NSCLC) with locoregional recurrences. To date, there is a lack of systematic reviews on safety or efficacy of NSCLC reirradiation and dedicated guidelines. This American Radium Society Appropriate Use Criteria Systematic Review and Guidelines provide practical guidance on thoracic reirradiation safety and efficacy and recommends consensus of strategy, techniques, and composite dose constraints to minimize risks of high-grade/fatal toxicities. Preferred Reporting Items for Systematic Reviews and Meta-Analyses systematic review assessed all studies published through May 2020 evaluating toxicities, local control and/or survival for NSCLC thoracic reirradiation. Of 251 articles, 52 remained after exclusions (3 prospective) and formed the basis for recommendations on the role of concurrent chemotherapy, factors associated with toxicities, and optimal reirradiation modalities and dose-fractionation schemas. Stereotactic body radiation therapy improves conformality/dose escalation and is optimal for primary-alone failures, but caution is needed for central lesions. Concurrent chemotherapy with definitive reirradiation improves outcomes in nodal recurrences but adds toxicity and should be individualized. Hyperfractionated reirradiation may reduce long-term toxicities, although data are limited. Intensity modulated reirradiation is recommended over 3D conformal reirradiation. Particle therapy may further reduce toxicities and enable safer dose escalation. Acute esophagitis/pneumonitis and late pulmonary/cardiac/esophageal/brachial plexus toxicities are dose limiting for reirradiation. Recommended reirradiation composite dose constraints (2 Gy equivalents): esophagus V60 <40%, maximum point dose (Dmax) < 100 Gy; lung V20 <40%; heart V40 <50%; aorta/great vessels Dmax < 120 Gy; trachea/proximal bronchial tree Dmax < 110 Gy; spinal cord Dmax < 57 Gy; brachial plexus Dmax < 85 Gy. Personalized thoracic reirradiation approaches and consensus dose constraints for thoracic reirradiation are recommended and serve as the basis for ongoing Reirradiation Collaborative Group and NRG Oncology initiatives. As very few prospective and small retrospective studies formed the basis for generating the dose constraint recommended in this report, further prospective studies are needed to strengthen and improve these guidelines.

Despite PACIFIC set a new milestone in the clinical management of unresectable stage III non-small cell lung cancer (NSCLC), it left some critical questions pending for clinical research: the efficacy of durvalumab in the real-world setting; the activity of less intensive regimens for frail populations; the role of targeted therapies in oncogene-addicted tumors; the selection of subsequent strategies at immunotherapy failure; the efficacy of novel and intensified treatments; the role of molecular biomarkers for patients' selection. This review aims to describe the evolving landscape of unresectable stage III NSCLC and provides an updated overview of the available evidence, analyzing lights and shadows emerging from recent clinical trials and discussing the most relevant challenges of post-PACIFIC era.

This multicenter single-arm confirmatory trial (CRES3T) investigated the efficacy and safety of S-1 + cisplatin and concurrent radical-dose radiotherapy followed by surgery in patients with a superior sulcus tumor.

Patients received induction therapy comprising three cycles of S-1 + cisplatin with concurrent radiotherapy (66 Gy in 33 fractions) followed by surgery. S-1 was administered orally at 40 mg/m2 twice/day on days 1-14, with an intravenous infusion of cisplatin (60 mg/m2) on day 1. The primary endpoint was the 3-year overall survival rate; key secondary endpoints included progression-free survival rate, objective response rate, pathological complete response rate, and toxicity.

Sixty-one patients with a superior sulcus non-small cell lung cancer received induction therapy. Radiological tumor invasion sites were the chest wall (n = 57), subclavian artery (n = 18), and subclavian vein (n = 10). Forty-nine patients underwent a lobectomy and combined resection of the involved structures. The objective and pathological complete response rates were 42 % (95 % confidence interval: 29-54 %) and 33 % (95 % confidence interval: 20-46 %), respectively. The 3-year overall survival and progression-free survival rates were 73.2 % (95 % confidence interval: 60.1-82.7 %) and 53.3 % (95 % confidence interval: 40.0-65.0 %), respectively. The patterns of first tumor relapse were locoregional only in one, distant metastasis only in 18, and both in four patients. Two pneumonia cases during induction therapy and one cardiac-arrest case on postoperative day 3 resulted in death.

Induction therapy using S-1 + cisplatin and concurrent radical-dose radiotherapy followed by surgery maximized local control and improved overall survival without impairing safety, potentially representing a new standard treatment.