Unresectable Locally Advanced Non-small Cell Lung Cancer Research Articles

Real-World Efficacy and Safety of Durvalumab Administration Following Chemoradiotherapy in Elderly Patients With Unresectable Locally Advanced Nonsmall Cell Lung Cancer: A Multicenter, Retrospective Study

BackgroundThe PACIFIC trial established durvalumab administration after chemoradiotherapy as the standard of care for unresectable locally advanced nonsmall cell lung cancer (LA-NSCLC). However, the efficacy and safety of durvalumab in elderly patients aged 75 years or above remains unclear. This study aimed to investigate the real-world efficacy and safety of durvalumab for LA-NSCLC, with a specific focus on elderly patients. Patients and MethodsWe reviewed 214 patients who received durvalumab out of 278 patients with unresectable LA-NSCLC who underwent chemoradiotherapy at 7 institutions between July 2018 and March 2022. Propensity score matching (PSM) analysis was performed to evaluate the efficacy of durvalumab in elderly patients. ResultsThe 2-year progression-free survival (PFS) and 2-year overall survival (OS) rates were 42.2% (95% confidence interval [CI], 34.7%-49.5%) and 77.1% (95% CI, 70.1-82.7%), respectively. Grade ≥ 3 immune-related adverse events (irAEs) occurred in 8.2% of patients. PSM analysis revealed that OS was significantly shorter in elderly patients (≥ 75 years) than in younger patients (< 75 years) (hazard ratio [HR]; 95% CI, 1.39-8.99; P = .008), whereas PFS did not differ significantly between the 2 groups (HR: 1.50, 95% CI, 0.84-2.68, P = .169). The frequency of irAEs did not differ between these groups. ConclusionsThe real-world efficacy and safety of durvalumab administration following chemoradiotherapy for LA-NSCLC coincided with the PACIFIC trial's findings. Disease control achieved with this protocol did not differ significantly between elderly and younger patients but had acceptable tolerability, demonstrating its benefit even in elderly LA-NSCLC patients aged 75 years or above.

Repeated dynamic [18F]FDG PET/CT imaging using a high-sensitivity PET/CT scanner for assessing non-small cell lung cancer patients undergoing induction immuno-chemotherapy followed by hypo-fractionated chemoradiotherapy and consolidative immunotherapy: report from a prospective observational study (GASTO-1067).

The study aims to investigate the role of dynamic [18F]FDG PET/CT imaging by high-sensitivity PET/CT scanner for assessing patients with locally advanced non-small cell lung cancer (LA-NSCLC) who undergo induction immuno-chemotherapy, followed by concurrent hypo-fractionated chemoradiotherapy (hypo-CCRT) and consolidative immunotherapy. Patients with unresectable LA-NSCLC are prospectively recruited. Dynamic [18F]FDG PET/CT scans are conducted at four timepoints: before treatment (Baseline), after induction immuno-chemotherapy (Post-IC), during hypo-CCRT (Mid-hypo-CCRT) and after hypo-CCRT (Post-hypo-CCRT). The primary lung tumors (PTs) are manually delineated, and the metabolic features, including the Patlak-Ki (Ki), maximum SUV (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) have been evaluated. The expressions of CD3, CD8, CD68, CD163, CD34 and Ki67 in primary lung tumors at baseline are assayed by immunohistochemistry. The levels of blood lymphocytes at four timepoints are analyzed with flow cytometry. Fifteen LA-NSCLC patients are enrolled between December 2020 and December 2022. Baseline Ki of primary tumor yields the highest AUC values of 0.722 and 0.796 for predicting disease progression and patient death, respectively. Patients are classified into the High FDG Ki group (n = 8, Ki > 2.779ml/min/100g) and the Low FDG Ki group (n = 7, Ki ≤ 2.779ml/min/100g). The High FDG Ki group presents better progression-free survival (P = 0.01) and overall survival (P = 0.025). The High FDG Ki group exhibits more significant reductions in Ki after hypo-CCRT compared to the Low FDG Ki group. Patients with a reduction in Ki > 73.1% exhibit better progression-free survival than those with a reduction ≤ 73.1% in Ki (median: not reached vs. 7.33months, P = 0.12). The levels of CD3+ T cells (P = 0.003), CD8+ T cells (P = 0.002), CD68+ macrophages (P = 0.071) and CD163+ macrophages (P = 0.012) in primary tumor tissues are higher in the High FDG Ki group. The High FDG Ki group has higher CD3+CD8+ lymphocytes in blood at baseline (P = 0.108), post-IC (P = 0.023) and post-hypo-CCRT (P = 0.041) than the Low FDG Ki group. The metabolic features in the High FDG Ki group significantly decrease during the treatment, particularly after induction immuno-chemotherapy. The Ki value of primary tumor shows significant relationship with the treatment response and survival in LA-NSCLC patients by the combined immuno-chemoradiotherapy regimen. ClinicalTrials.gov. NCT04654234. Registered 4 December 2020.

Radiation therapy (RT)-free pembrolizumab plus chemotherapy (P+C) for PD-L1 TPS ≥50% locally advanced non-small cell lung cancer (LA-NSCLC): Primary analysis from multicenter single arm phase II study (Evolution trial; WJOG11819L).

LBA8050 Background: Standard of care for unresectable LA-NSCLC is chemoradiation therapy (CRT) followed by durvalumab (D). Survival curves of P monotherapy/P+C for PD-L1 TPS ≥50% stage IV NSCLC suggested possible comparable survival to CRT for stage III patients (pts). Moreover, some studies of neoadjuvant C+immunotherapy (I) for stage III pts have demonstrated high pathological complete response and major pathological response rates, implying potentially outstanding efficacy of C+I for earlier stage. We thus hypothesized P+C without RT in PD-L1 ≥50% LA-NSCLC pts provides a comparable efficacy to CRT followed by D while avoiding CRT-induced severe toxicities. Methods: This is a phase II study conducted by West Japan Oncology Group. P with platinum plus pemetrexed (PEM) (non-squamous) or P with carboplatin plus nab-paclitaxel (squamous) was administered every 3 weeks without RT. After four cycles of induction P+C, P with PEM (non-squamous) or P alone (squamous) was continued until progression or 2 years. The primary endpoint was 2 year-PFS rate (threshold/expected: 20%/45%). Results: Between May 2020 and February 2022, 21 pts were enrolled. Median age was 73 (range, 53-89). Stage IIIA/B/C included 11 (52%)/7 (33%)/3 (14%), respectively. Histologic subtypes were 14 (67%) adenocarcinoma, 5 (24%) squamous cell carcinoma, and 2 (10%) others. Median follow-up period was 29.9 (range, 0.3-44.2) months. Median number of P administrations was 30 (range, 1-35). The primary endpoint was met with 2-year PFS rate of 67% (90% CI: 46-83%). At the time of data cut-off, 13 (62%) of 21 pts were still progression-free. Median PFS and OS were not reached. Two-year OS rate was 85%. Centrally reviewed tumor response: 8 (38%) CR; 9 (43%) PR; 3 (14%) SD; and 1 (5%) NE were confirmed, resulting in overall response rate (ORR) of 81% and disease control rate of 95%. ORRs/2-year PFS rates of PD-L1 TPS 50-79% and 80-100% were 67%/56% and 92%/75%, respectively. Non-hematological AEs ≥grade 3 were observed in 11 (52%) pts, including: 2 (10%) pneumonitis; 2 (10%) pneumonia; 1 (5%) diarrhea; 1 (5%) ALT elevation; and 1 (5%) acute heart failure. There was one (5%) grade 5 AE (pneumonia). Conclusions: RT-free P+C provided long-lasting responses in approximately two-thirds of pts. Higher PD-L1 TPS cases achieved higher RR, including some CRs and higher 2-year PFS rate. To confirm our hypothesis that RT-free P+C can be a less toxic curative option in selected LA-NSCLC pts with PD-L1 TPS ≥50%, further data is warranted. Clinical trial information: NCT04153734 .

Global retrospective study comparing consolidation ALK tyrosine kinase inhibitors (TKI) to durvalumab (durva) or observation (obs) after chemoradiation (CRT) in unresectable locally-advanced ALK+ non-small cell lung cancer (NSCLC).

8013 Background: For patients (pts) with unresectable locally-advanced NSCLC, standard of care involves durva consolidation after concurrent CRT, although its benefit in ALK+ tumors is unclear. The ALINA trial demonstrated adjuvant efficacy of alectinib in resected ALK+ NSCLC, but the optimal consolidation strategy for unresectable locally-advanced ALK+ NSCLC remains elusive. Methods: This multi-institutional international retrospective analysis included pts with stage III unresectable ALK+ NSCLC who received an ALK TKI, durva, or obs alone after concurrent CRT between 2015-2022. Baseline characteristics of age, sex, smoking history, and PD-L1 status were collected. Clinical outcomes including real-world progression-free survival (rw-PFS), overall survival (OS), and treatment-related adverse events (trAE) as defined using CTCAE 5.0 were assessed, and multivariate cox regression models were performed. Results: Sixty-four pts across 16 institutions were included. The median age was 57 (IQR 49-66) and 61% were females. The majority had adenocarcinoma (97%) and had never smoked (58%). 15 received ALK TKI (10 alectinib, 3 crizotinib, 1 brigatinib, 1 lorlatinib), 30 received durva, and 19 received obs alone. There was no significant difference in stage of cancer (IIIA, B, or C) or PD-L1 status among groups. After adjusting for stage and age at CRT initiation, median rw-PFS was significantly longer for ALK TKI (rw-PFS not reached [NR], 95% CI 22.7-NR) vs durva (11.3 months (mo), 95% CI 9.2-18.5, p= 0.005, HR = 0.12) or obs (7.4 mo, 95% CI 3.4-12.5, p &lt; 0.0001). Two (13%) pts progressed on ALK TKI. 25 pts (83%) progressed on durva leading to treatment with ALK TKI in 23, and 18 (95%) progressed while under obs leading to treatment with ALK TKI in 15. 3-year OS was 100% for ALK TKI vs 90.5% for durva vs 63.5% for obs. Median OS was NR (95% CI NR-NR) for both ALK TKI and durva vs 70.6 mo (24.9-NR) in the obs group ( p= 0.03 for both ALK TKI and durva compared to obs). Median duration of therapy was 24.7 mo with ALK TKI and 6.5 mo with durva. Grade ≥3 trAE occurred in 27%, 7%, 6% of pts treated with ALK TKI (1 fatigue, 1 diarrhea, 1 hyperbilirubinemia, 1 pneumonitis), durva (1 fatigue, 1 neutropenia), and obs (1 neutropenia) respectively. Treatment discontinuation due to toxicity occurred in 4 (27%) with ALK TKI and in 3 (10%) with durva. Conclusions: In this retrospective study of stage III ALK+ NSCLC, consolidation ALK TKI demonstrated clinically meaningful improvement in PFS and OS over durva and obs, while showing a slightly higher rate of trAE over dura and obs. Furthermore, we show a high rate of progression following CRT alone in ALK+ NSCLC. These findings underscore the need for prospective molecularly driven trials to determine the optimal consolidation therapy for unresectable ALK+ NSCLC.

Induction immunochemotherapy followed by definitive chemoradiotherapy for unresectable locally advanced non-small cell lung cancer: a multi-institutional retrospective cohort study.

This study aimed to evaluate the efficacy and safety of induction immunochemotherapy followed by definitive chemoradiotherapy (CRT) for unresectable locally advanced non-small cell lung cancer (LA-NSCLC). We identified unresectable stage III NSCLC patients who received induction immunochemotherapy. Overall survival (OS) and progression-free survival (PFS) were the primary endpoints. From February 2019 to August 2022, 158 patients were enrolled. Following the completion of induction immunochemotherapy, the objective response rate (ORR) and disease control rate (DCR) were 52.5% and 83.5%, respectively. The ORR of CRT was 73.5%, representing 68.4% of the total cohort. The median PFS was 17.8 months, and the median OS was 41.9 months, significantly higher than in patients who received CRT alone (p<0.001). Patients with concurrent CRT demonstrated markedly improved PFS (p=0.012) and OS (p=0.017) than those undergoing sequential CRT. Additionally, those with a programmed-death ligand 1 (PD-L1) expression of 50% or higher showed significantly elevated ORRs (72.2%vs. 47.2%, p=0.011) and superior OS (median 44.8vs. 28.6 months, p=0.004) compared to patients with PD-L1 expression below 50%. Hematologic toxicities were the primary severe adverse events (grade ≥ 3) encountered, with no unforeseen treatment-related toxicities. Thus, induction immunochemotherapy followed by definitive CRT demonstrated encouraging efficacy and tolerable toxicities for unresectable LA-NSCLC.

Chemotherapy-free radiotherapy combined with immune checkpoint inhibitors: a new regimen for locally advanced non-small cell lung cancer?

Maintenance immunotherapy after concurrent chemoradiotherapy remains the standard therapeutic approach in patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC). The efficacy of pembrolizumab without chemotherapy in stage IV NSCLC has incited interest in similar approaches for LA-NSCLC. Several recent investigations involving the synergistic potential of immunotherapy combined with radiotherapy (iRT) have generated encouraging results. This review discusses the existing studies and prospective directions of chemotherapy-free iRT strategies in unresectable LA-NSCLC. Although the initial findings of chemotherapy-free iRT strategies have shown promising efficacy, we must consider the methodologic limitations of current studies and the myriad of challenges that accompany the implementation of chemotherapy-free iRT. These challenges include determining the optimal dose and fractionation, precise target volume delineation, and identification of additional suitable patient cohorts. Furthermore, the feasibility of chemotherapy-free iRT as a novel treatment modality for select patients with LA-NSCLC is contingent upon validation through randomized phase III trials.

Contribution of Enhanced Locoregional Control to Improved Overall Survival with Consolidative Durvalumab after Concurrent Chemoradiotherapy in Locally Advanced Non-Small Cell Lung Cancer: Insights from Real-World Data.

This study aimed to assess the real-world clinical outcomes of consolidative durvalumab in patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC) and to explore the role of radiotherapy in the era of immunotherapy. This retrospective study assessed 171 patients with unresectable LA-NSCLC who underwent concurrent chemoradiotherapy (CCRT) with or without consolidative durvalumab at Asan Medical Center between May 2018 and May 2021. Primary outcomes included freedom from locoregional failure (FFLRF), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS). Durvalumab following CCRT demonstrated a prolonged median PFS of 20.9 months (p=0.048) and a 3-year FFLRF rate of 57.3% (p=0.008), compared to 13.7 months and 38.8%, respectively, with CCRT alone. Furthermore, the incidence of in-field recurrence was significantly greater in the CCRT-alone group compared to the durvalumab group (26.8% vs. 12.4%, p=0.027). While median OS was not reached with durvalumab, it was 35.4 months in patients receiving CCRT alone (p=0.010). Patients positive for programmed cell death ligand 1 (PD-L1) expression showed notably better outcomes, including FFLRF, DMFS, PFS, and OS. Adherence to PACIFIC trial eligibility criteria identified 100 patients (58.5%) as ineligible. The use of durvalumab demonstrated better survival regardless of eligibility criteria. The use of durvalumab consolidation following CCRT significantly enhanced locoregional control and OS in patients with unresectable LA-NSCLC, especially in those with PD-L1-positive tumors, thereby validating the role of durvalumab in standard care.

Induction Immunochemotherapy Followed by Definitive Chemoradiotherapy for Unresectable Locally Advanced Non-Small Cell Lung Cancer

Concurrent chemoradiotherapy (cCRT) followed by immune checkpoint inhibitors (ICIs) consolidation is the current standard of care for unresectable locally advanced non-small cell lung cancer (LA-NSCLC). However, most patients diagnosed with unresectable LA-NSCLC will not meet the criteria for adjuvant ICIs in the real world. Theoretically, adjusting the ICIs from the consolidation phase to the induction setting could greatly improve the patient' s compliance to receive ICIs therapy. Consequently, we performed this study to evaluate the efficacy and safety of induction ICIs and chemotherapy followed by definitive CRT for unresectable LA-NSCLC. A total of 102 unresectable stage III NSCLC patients who received neoadjuvant immunochemotherapy followed by definitive CRT between 2019 and 2022 were identified. The primary endpoint of this study was to determine the efficacy of this treatment pattern, including overall survival (OS) and progression free survival (PFS). Disease control rate (DCR) and toxicities were the secondary objective. The median age was 64 years (range 34-81), including 58 (56.9%) squamous cell carcinoma and 37 (36.3%) non-squamous cell carcinoma patients. There were 34 (33.3%), 39 (38.2%) and 29 (28.4%) patients with stage IIIA, IIIB and IIIC disease, respectively. The DCR at the end of induction immunochemotherapy was 87.3%. The median PFS was 20.4 months (95% CI, 15.7-25.1), with PFS rates of 90.1% at 6 months, 70.4% at 1 year, 55.2% at 18 months and 41.9% at 2 years. The rates of OS were 92.8%, and 76.2% at 1 year, and 2 years, respectively, and the median OS was not reached. For patients without progression before CRT, the median OS was also not reached, and the median PFS was 21.3 months. Patients receiving concurrent CRT manifested significantly better OS, compared with sequential CRT (12-month OS, 89.4% vs. 100.0%; 24-month OS, 70.2% vs. 87.3%; P = 0.030). Patients with PD-L1 expression of 50% or more manifested significantly higher partial response rate (70.4% vs. 45.3%, P = 0.033), along with better survival (median PFS, 17.3 months vs. NR, P = 0.034; median OS, 26.5 months vs. NR, P = 0.037), compared to those less than 50%. Treatment was well tolerated, with an incidence of 4.9% for grade 3 or greater pneumonitis or radiation pneumonitis (RP). The most common severe (grade ≥3) adverse events were hematologic toxicities and no unexpected treatment related toxicities occurred. Induction immunochemotherapy followed by definitive CRT showed promising efficacy and tolerable toxicities for unresectable LA-NSCLC, especially for those with tumoral PD-L1 expression over 50%.

Improved Prediction of Chemoradiation and Immune Checkpoint Blockade Efficacy with Dynamic bTMB Combined with ctDNA in Unresectable Locally Advanced NSCLC

Consolidation durvalumab after definitive chemoradiation therapy (CRT) has become the new standard of care for patients with unresectable locally advanced non-small-cell lung cancer (LA-NSCLC). However, only a fraction of patients can benefit from it, and current decision-making procedures have limited accuracy. Blood-based tumor mutational burden (bTMB) is a promising biomarker, but whether bTMB alone or combined with circulating tumor DNA (ctDNA) can predict the efficacy of definitive CRT and immune checkpoint inhibitors (ICIs) in patients with LA-NSCLC remains unclear. This cohort study enrolled patients diagnosed with unresectable LA-NSCLC from 2018 to 2022. Patients were assigned to the cohort A receiving definitive CRT alone (intensity modulated radiation therapy or volumetric modulated arc therapy with the prescribed dose of 60 Gy, concurrently or sequentially with two or more cycles of platinum-based doublet chemotherapy), or cohort B undergoing definitive CRT and immunotherapy. Peripheral blood specimens were collected before and after CRT and subjected to next-generation sequencing panel to analyze ctDNA and bTMB. The dynamic change in bTMB (∆bTMB) was calculated as the bTMB level after CRT minus the baseline bTMB level. Potential correlations were identified by Spearman's correlation tests and expressed as R coefficients. Time-dependent receiver operating characteristic curves and areas under the curve (AUCs) were employed to evaluate the predictive power of different models on survival. A total of 73 LA-NSCLC patients were included, with 70 (95.9%) at stage III and 3 at stage II (4.1%). Thirty-six patients (49.3%) assigned to the cohort A were treated with CRT alone and 37 (50.7%) in the cohort B receiving CRT and ICIs. Patients with CRT + ICIs in the cohort B showed significantly improved overall survival (OS; P < 0.01) and progression-free survival (PFS; P = 0.02) than those with CRT alone. Baseline bTMB at cutoff values of 4 to 22 did not predict outcomes (all P > 0.10), while patients with increased bTMB (∆bTMB > 0) after CRT had significantly worse OS and PFS (both P < 0.01) than those with decreased or stable bTMB (∆bTMB ≤ 0). ∆bTMB was independent of the ctDNA level after CRT (P = 0.76, R = -0.04). Patients were further divided into 3 groups based on ∆bTMB and post-CRT ctDNA (∆bTMB > 0/detectable ctDNA vs. ∆bTMB ≤ 0/detectable ctDNA vs. ∆bTMB ≤ 0/undetectable ctDNA), and significant survival differences were observed in the pairwise comparisons of 3 groups (all P < 0.05). The model of ∆bTMB combined with post-CRT ctDNA status exhibited the optimal predictive power on both OS (AUC = 0.80) and PFS (AUC = 0.75) and outperformed each factor, which had been respectively validated in the cohort A and B as well. Dynamic bTMB (∆bTMB) combined with post-CRT ctDNA status is a novel and effective biomarker model of predicting survival outcomes in LA-NSCLC patients treated with CRT ± ICIs, and outperforms each individual feature.

Radiation therapy (RT)-free pembrolizumab plus chemotherapy (P+C) for PD-L1 TPS ≥50% locally advanced non-small cell lung cancer (LA-NSCLC): An early report analyzing depth of response from multicenter single arm phase II study (Evolution trial: WJOG11819L).

8544 Background: Standard of care for unresectable LA-NSCLC is chemoradiation therapy (CRT) followed by durvalumab (D). Survival curves of P monotherapy/P+C for PD-L1 TPS ≥50% stage IV NSCLC suggested possible comparable survival to CRT for stage III patients (pts). Moreover, some studies of neoadjuvant C+immunotherapy (I) for stage III pts have demonstrated high pCR and MPR rates, implying potentially outstanding efficacy of C+I for earlier stage. We thus hypothesized P+C without RT in PD-L1 ≥50% LA-NSCLC pts provides a comparable efficacy to CRT followed by D while avoiding CRT-induced severe toxicities. Methods: This early report focuses on depth of response in a phase II study by WJOG. P with platinum plus pemetrexed (PEM) (non-squamous) or P with carboplatin plus nab-paclitaxel (squamous) was administered every 3 weeks without RT. After four cycles of induction P+C, P with PEM (non-squamous) or P alone (squamous) was continued until progression or 2 years. The primary endpoint was PFS rate at 2 years. Results: Between May 2020 and February 2022, 21 pts were enrolled. Median age was 74 (range, 53-89). Stage IIIA/B/C included 12 (57%)/6 (29%)/3 (14%), respectively. Histologic subtypes were 13 (62%) adeno, 5 (24%) squamous, and 3 (14%) others. Investigator-assessed best response: 8 (38%) CR; 10 (48%) PR; 2 (10%) SD; and 1 (5%) NE were confirmed, resulting in response rate (RR) of 86% and disease control rate of 95%. RR of TPS 50-79% and 80-100% were 78% and 92%, respectively. Deep response (DR): defined as tumor shrinkage ≥80% was obtained in 12 (57%) of 21 pts. DR was accomplished in 4 (44%) of 9 TPS 50-79% and 8 (67%) of 12 TPS 80-100%. Median time to response was 43 (range, 41-92) days. Early tumor shrinkage (ETS): PR-in at the time of first CT evaluation (6 weeks) was achieved in 16 (89%) of 18 CR+PR pts. At the time of data cut-off, median follow-up period was 18.5 (range, 0.3-29.0) months, and 14 (67%) of 21 pts were progression-free. All 12 pts achieving DR, including all 8 CR were progression-free, also in 14 (88%) of 16 ETS pts. Three pts after local progression received salvage definitive-CRT. Median number of P administrations was 20 (range, 1-35). AEs ≥grade 3 were observed in 11 (52%) pts, including: 2 (10%) pneumonitis; 2 (10%) pneumonia; 1 (5%) diarrhea; 1 (5%) ALT elevation; and 1 (5%) acute heart failure, excluding hematological AEs. There was one (5%) possible grade 5 AE (pneumonia). Conclusions: RT-free P+C exerted a notably high RR, including some CRs. The deeper/earlier response and higher PD-L1 TPS could be associated with the higher progression-free incidence at the data cut-off. To investigate our hypothesis: RT-free P+C can be a less toxic curative option in selected LA-NSCLC pts with PD-L1 TPS ≥50%, further matured data is warranted. Clinical trial information: NCT04153734 .

CtDNA for clonal evolution surveillance and therapeutic efficacy prediction in unresectable locally advanced non-small cell lung cancer under radiotherapy.

e20555 Background: Therapeutic efficacy differs across unresectable locally advanced non-small cell lung cancer (LA-NSCLC) patients receiving definitive radiotherapy/chemoradiotherapy (RT/CRT), but the underlying resistance mechanism, clonal evolution and molecular prognostic factors remain poorly understood. Methods: Unresectable LA-NSCLC patients treated with definitive RT/CRT were consecutively enrolled between May 2018 and November 2020. Next-generation sequencing covering 474 cancer-relevant genes was performed on plasma ctDNA collected at pre-treatment (TP0), 4-week post-RT (TP1), 1-month post-RT (TP2), 3-month post-RT (TP3), and progression (TP4). Main study endpoints included disease progression, progression-free survival (PFS), death from any cause, overall survival (OS), distant metastasis and distant metastasis free survival. Fisher’s exact test and two-sample t-tests were performed to compare the frequencies and means of independent groups, respectively. The median follow-up time was estimated using the reverse Kaplan-Meier method. Hazard ratios (HR) with 95% confidence intervals (CI) were estimated by Cox proportional hazards models. Results: A total of 46 patients were included (median age: 63 [range: 40–80], males: 87%, clinical stage IIIB: 52%, squamous cell carcinoma: 54%, TP0 ctDNA shedding: 63%, consolidation immunotherapy: 33%). Twenty-nine (63%) patients developed disease progression by the end of follow-up (median follow-up: 23.7 months), with median PFS and OS being 15.5 and 25.4 months, respectively. The polymerase epsilon ( POLE) mutational signature at TP0 indicated inferior PFS (HR: 5.32, 95% CI: 1.83–15.45) and worse OS (HR: 20.68, 95% CI: 3.94–108.62). Notably, newly-discovered/lost mutations were rarely observed at TP4 when compared to TP0. Patients with a high ratio of mean over max variant allele frequency (m/mVAF) in TP0 samples, indicative of a clonal predominant tumor with a low subclone fraction ( P&lt; 0.01), had relatively poor OS, compared to patients with low m/mVAF (HR: 2.92, 95% CI: 0.82–10.46) or undetectable ctDNA (HR: 3.39, 95% CI: 0.98–11.75). The prognostic value was validated in an independent publicly available dataset of 431 LA-NSCLC patients receiving definitive RT/CRT, showing patients with high m/mVAF demonstrated worse OS than those with low m/mVAF (HR: 1.43, 95% CI: 1.08–1.89). Additionally, increased m/mVAF between TP0 and TP1 indicated an elevated risk for disease progression ( vs. non-increase, HR: 3.49, 95% CI: 1.20–10.16), especially for distant metastasis ( vs. non-increase, HR: 2.85, 95% CI: 0.84–9.69). Conclusions: Our findings demonstrated the clinical value of plasma ctDNA and its derived molecular features in delineating clonal evolution, monitoring therapeutic resistance, and predicting prognosis of LA-NSCLC under definitive RT.

Real-world treatment patterns and clinical outcomes in EGFR-mutant locally advanced lung adenocarcinoma: A multi-center cohort study

ObjectiveTo investigate the optimal management of patients with epidermal growth factor receptor gene (EGFR) mutant locally advanced non-small cell lung cancer (LA-NSCLC). MethodsPatients with unresectable stage III lung adenocarcinoma (LAC) harboring EGFR mutations from 2012 to 2018 were analyzed retrospectively, and were categorized into three groups according to the primary treatment: chemoradiotherpy (CRT) (group 1), combined radiation therapy (RT) and EGFR-tyrosine kinase inhibitors (TKI) with/without chemotherapy (group 2), and EGFR-TKI alone until tumor progression (group 3). Inverse probability of multiple treatment weighting (IPTW) of propensity score was used to compare overall survival (OS) and progression free survival (PFS) between treatments and account for confounding. ResultsA total of 104, 105, and 231 patients were categorized into groups 1, 2, and 3, respectively. After IPTW adjustment, the median PFS for each group was 12.4, 26.2, and 16.2 months (log-rank P < 0.001), and the median OS was 51.0, 67.4 and 49.3 months (log-rank P = 0.084), respectively. Compared with those in group 1, patients in group 2 had significantly improved PFS [adjusted hazard ratio HR (aHR), 0.40; 95% confidence interval (CI): 0.29, 0.54; P < 0.001] and OS (aHR, 0.61; 95% CI: 0.38, 0.98; P = 0.039). Patients in group 3 had prolonged PFS (aHR, 0.66; 95% CI: 0.50, 0.87; P = 0.003), but not OS (aHR, 0.90; 95% CI: 0.62, 1.32; P = 0.595). Doubly robust IPTW analysis and multivariable Cox regression analysis yielded similar findings. ConclusionsEGFR-TKIs after chemoradiation or combined with radiation alone correlated with the longest PFS and OS (versus CRT or TKIs alone) in patients with EGFR-mutant unresectable LA-NSCLC. Well-designed prospective trials were warranted.

Early recurrence factors in patients with stage III non-small cell lung cancer treated with concurrent chemoradiotherapy.

The clinical characteristics and risk factors for cancer recurrence have not been well evaluated regarding early recurrence in patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC) who receive concurrent chemoradiotherapy (CRT). The aim of this study was to determine the clinical characteristics and risk factors of patients with stage III unresectable LA-NSCLC treated with CRT who developed early recurrence. We retrospectively reviewed the clinical records of 46 patients diagnosed with stage III unresectable LA-NSCLC treated with CRT at our center between July 2012 and July 2021. A tumor proportion score (TPS) < 50% was defined as "low expression" and a TPS > 50% was defined as "high expression." A total of 17 (37.0%) patients had a confirmed recurrence within 1year of treatment. More patients had a lower body mass index in the early recurrence group than in the later recurrence group (p= 0.038). A higher number of patients in the late recurrence group underwent surgery after CRT (p= 0.036). Patients with a higher TPS were more likely to experience late recurrence than early recurrence (p= 0.001), whereas more patients with stage N3 disease were in the early recurrence group (p= 0.011). Multivariate analysis identified lower TPS expression as an independent risk factor for early recurrence after CRT. Overall survival was prolonged in the late recurrence group (p < 0.001). A lower TPS may be a predictor of early recurrence after CRT in patients with LA-NSCLC. These patients should be closely monitored for post-treatment recurrence.

Patterns of Failure by Driver Mutation Status for Patients with Locally Advanced Non-Small Cell Lung Cancer Treated with Chemoradiation and Consolidative Durvalumab

<h3>Purpose/Objective(s)</h3> The standard of care for patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC) is concurrent chemoradiation (CRT) followed by consolidative durvalumab. Increasingly, mutational profiling has been used to guide treatment decisions. In this study, we investigated whether driver mutation status influences the patterns of failure and rates of oligometastatic disease. <h3>Materials/Methods</h3> Using a single institution database, we identified patients who were treated with CRT followed by consolidative durvalumab for LA-NSCLC from June 2017 to May 2020 and divided them by whether they had driver mutations as defined by EGFR exon 19 deletion, EGFR exon 20 insertion, HER2 exon 20 insertion, EGFR exon 21 mutation (L858R), ALK-EML4 fusion, MET exon 14 skipping, NTRK2 fusion, or KRAS mutation. There mutations were all targetable with the exception that only KRAS G12C is a targetable KRAS mutation. We then identified patients who had disease progression and recorded their patterns of failure (distant vs locoregional) and oligometastatic status (3 or fewer sites). These rates were compared by driver mutation status using Chi-squared tests. Comparisons of time to second progression (PFS2) by oligometastatic and driver mutation status were made using Kaplan-Meier analyses. <h3>Results</h3> The 63 patients in our cohort (of which 36 had driver mutations) had a median follow up of 21.5 months, age of 64.8 yrs, and ECOG of 1 at completion of CRT. 52% were female, 86% had a history of smoking, and 87% were white. 65% had adenocarcinoma. All were treated with concurrent CRT with radiation doses ranging from 60Gy to 77Gy. All received at least one dose of consolidative durvalumab prior to disease progression. A similar proportion of first progressions were distant failures in patients with driver mutations and those without (64% vs. 59%, p=0.71). They also had similar rates of oligometastatic disease (28% vs 48%, p=0.09). Patients with oligometastatic disease did not have improved PFS2 (5.9 months vs 5.9 months, p=0.76) compared to those with polymetastatic disease. However, oligometastatic patients with targetable driver mutations who received salvage local therapy (surgery and/or radiation) without tyrosine kinase inhibitors (TKIs) had dramatically worse PFS2 (4.1 months vs 21.4 months, p=0.01) compared to all patients with driver mutations. Conversely, the use of local therapy without systemic therapy did not lead to worse PFS2 in oligometastatic patients without targetable driver mutations (3.5 months vs 4.5 months, p=0.46). <h3>Conclusion</h3> We show similar patterns of failure and rates of oligoprogression for unresectable LA-NSCLC patients treated with concurrent CRT and consolidative durvalumab regardless of driver mutation status. Initial oligometastatic disease did not decrease the likelihood of subsequent progression. Oligometastatic patients with targetable driver mutations should not receive salvage local therapy alone without initiation of TKIs.

EP05.01-004 Induction Chemoimmunotherapy before Definitive Chemoradiotherapy for Large-Volume Unresectable Locally Advanced NSCLC

Although outcomes of locally advanced non-small-cell lung cancer (LA-NSCLC) have been greatly improved since the practice-changing results from the PACIFIC trial, treatments for large-volume LA-NSCLC remain challenging. We investigated induction chemoimmunotherapy and definitive chemoradiotherapy (CRT) for unresectable LA-NSCLC patient subgroups with larger tumor bulk, aiming to improve survival by optimizing patient selection and individualizing combination treatments.

Efficacy of Thymosin α1 in Management of Radiation Pneumonitis in Patients With Locally Advanced Non-Small Cell Lung Cancer Treated With Concurrent Chemoradiotherapy: A Phase 2 Clinical Trial (GASTO-1043)

To evaluate the efficacy of thymosin α1 in management of radiation pneumonitis (RP) in patients with locally advanced non-small cell lung cancer (LANSCLC) treated with concurrent chemoradiotherapy (CCRT). This phase 2, single-arm trial enrolled patients with unresectable LANSCLC of 18 to 75 years' old and an Eastern Cooperative Oncology Group performance status of 0 to 1. Eligible patients received definitive CCRT and weekly thymosin α1 from the start of CCRT until 2 months after CCRT. Patients were administered 51 Gy in 17 daily fractions or 40 Gy in 10 daily fractions in the first course followed by a re-evaluation and those patients without disease progression had an adaptive plan of 15 Gy in 5 daily fractions or 24 Gy in 6 daily fractions as a boost. Concurrent chemotherapy consisted of weekly docetaxel (25 mg/m2) and nedaplatin (25 mg/m2) during radiation therapy. The primary endpoint was the incidence of Grade (G) ≥2 RP. Secondary endpoints included the incidence of late pulmonary fibrosis, total lymphocyte count (TLC), serum C-reactive protein (CRP) levels, and the composition of gut microbiota. TLC and CRP data were collected at baseline, 2 to 3 weeks during CCRT, the end of CCRT, 2 and 6 months after CCRT. Fecal samples were collected at baseline and the end of CCRT. Patients treated with CCRT but without thymosin α1 intervention during the same period were selected as the control group by the propensity score matching method. Sixty-nine patients were enrolled in the study, and another 69 patients were selected as the control group. The incidence of G≥2 RP was lower in the study group compared with control cases (36.2% vs 53.6%, P=.040). G1 late pulmonary fibrosis occurred in 2 (3.7%) patients of the control group compared with no event in the study group (P=.243). Compared with the control group, the incidence of G3 to G4 lymphopenia (19.1% vs 62.1%, P < .001) was lower, and the median TLC nadir (0.51 k/µL vs 0.30 k/µL, P < .001) was higher in the study group. The proportion of patients with maximum CRP ≥100 mg/L was lower in the study group (13.8% vs 29.7% P=.029). The diversity and community composition of the gut microbiota were not significantly different between the 2 groups. Administration of thymosin α1 during and after CCRT was associated with significant reductions in G≥2 RP and G3 to G4 lymphopenia in patients with LANSCLC compared with historic controls.

Baseline PD-L1 expression and tumour-infiltrated lymphocyte status predict the efficacy of durvalumab consolidation therapy after chemoradiotherapy in unresectable locally advanced patients with non-small-cell lung cancer

BackgroundChemoradiotherapy (CRT) followed by durvalumab treatment improved prognosis in unresectable locally advanced non-small-cell lung cancer (LA-NSCLC). This study aimed to evaluate whether the status of the immune-related tumour microenvironment (TME) at baseline associates with the efficacy. MethodsThis retrospective study evaluated immune-related TME factors, including programmed cell death ligand 1 (PD-L1) (clone: 22C3) expression on tumour cells and the density of CD8-positive tumour-infiltrating lymphocytes (TILs) at pre-CRT in patients with unresectable LA-NSCLC treated with CRT only (CRT alone group) and those treated with CRT followed by durvalumab (Durva group). ResultsA total of 551 patients were included (N = 113 in the Durva group). Progression-free survival (PFS) in the Durva group was significantly greater than that in the CRT alone group (not reached [NR] vs 12.9 months; p = 0.002). In the CRT alone group, neither PD-L1 expression nor TIL status affected PFS; in contrast, in the Durva group, high density of CD8-positive TILs (TILHigh ≥100/mm2) and PD-L1-positive expression (tumour proportion score ≥1%; PD-L1+) was significantly associated with longer PFS (TIL: NR vs 9.5 months; p = 0.002; and PD-L1: NR vs 7.7 months; p = 0.003). On the other hand, in patients with epidermal growth factor receptor mutations or anaplastic lymphoma kinase rearrangements, there was no significant difference in PFS between the groups (Durva vs CRT alone: 9.9 months vs 14.0 months; p = 0.77). ConclusionsPD-L1+ and TILHigh at baseline could be predictive markers of the efficacy of CRT followed by durvalumab.

Circulating Tumor DNA Dynamics Predict Prognosis of Locally Advanced Non-Small Cell Lung Cancer Patients Treated With Definitive Chemoradiotherapy

Locally advanced non-small cell lung cancer (LA-NSCLC) has strong tumor heterogeneity. Postradiotherapy concentration of circulating tumor DNA (ctDNA) has been demonstrated a promising prognostic biomarker of LA-NSCLC and might be helpful in assisting consolidation decision-making. However, it is widely acknowledged that many biomarkers are specific to certain patient populations. Therefore, we performed this prospective study in Chinese patients with LA-NSCLC to evaluate the prognostic role of ctDNA.We consecutively enrolled patients with unresectable LA-NSCLC. Plasma samples were prospectively collected at different time point if obtained (1) baseline (pretreatment), (2) the fourth week during radiotherapy (RT), and (3) one-month post RT. All plasma specimens were subjected to next-generation sequencing panel of 474 cancer-related genes. Plasma samples with at least 1 variant detected were defined as ctDNA+. A landmark analysis was used to assess predictive value of ctDNA clearance at the time point of one-month post RT. Nonparametric test was used to compare ctDNA concentrations among groups. The Kaplan-Meier method was used to estimate survival distributions, Cox model to estimate hazard ratios and confidence intervals, and log-rank test to estimate P value.A total of 35 patients treated with definitive chemoradiotherapy (CRT) were enrolled. The median follow-up from diagnosis was 16 months. At baseline timepoint, 21 patients with ctDNA+ and 14 patients with ctDNA-. For ctDNA+ patients, ctDNA concentration (ng/ml) was significantly higher with increasing clinical stage (stage IIIA vs stage IIIB vs stage IIIC, 0.345 vs 0.580 vs 3.630, P = 0.007). Both progression free survival (PFS) and overall survival (OS) was not significantly different between ctDNA- and ctDNA+ group at baseline timepoint. However, at the time point of one-month post RT, patients with ctDNA- had significantly higher PFS (median: NA vs 7 months; HR 0.205, 95% CI: 0.066∼0.637; P = 0.002) and OS (HR 0.065, 95% CI: 0.008∼0.541; P = 0.001). Kinetic changes in ctDNA concentrations were analyzed in 16 pts with matching baseline and one-month post RT specimens. Of these 16 cases with detectable ctDNA at baseline, 50% (8/16) became undetectable at one-month post RT ("ctDNA clearance"), all these 8 patients were alive and nonrecurrent during the following-up. ctDNA clearance was associated with significantly higher PFS (P = 0.003) and OS (P = 0.016) compared with ctDNA residual patients.For LA-NSCLC receiving CRT, ctDNA concentration was significantly higher with increasing clinical stage (IIIA vs IIIB vs IIIC). Baseline ctDNA+/- seemed not a prognosis factor, whereas ctDNA- or ctDNA clearance at the time of one-month post RT was associated with significantly superior PFS and OS. More enrolled patients are needed to update and validate these results.NCT04014465.

A Phase II Trial of Primary Tumor SBRT Boost Prior to Concurrent Chemoradiation for Locally-Advanced Non-Small Cell Lung Cancer (LA-NSCLC)

Primary tumor failure is common in patients treated with chemoradiation (CRT) for unresectable LA-NSCLC. Stereotactic body radiation therapy (SBRT) yields high rates of primary tumor control in Stage I NSCLC. This trial tested an SBRT boost to the primary tumor prior to the start of CRT to improve primary tumor control (PTC).Patients with LA-NSCLC with primary tumor ≤10 cm were enrolled on a prospective phase II trial testing an SBRT boost in 2 fractions (central 6 Gy x 2, peripheral 8 Gy x 2) immediately followed by standard concurrent CRT (60 Gy in 30 fractions). Patients were staged with PET-CT, brain MRI, and underwent 4D-CT simulation for radiation planning using a customized immobilization device that enabled radiation planning for the sequential delivery of the SBRT boost and conventionally-fractionated radiation from the same CT dataset. Chemotherapy was carboplatin/paclitaxel (C/P) or cisplatin/etoposide. For patients receiving C/P, consolidation C/P for 2 cycles was given at the discretion of the medical oncologist. The trial was later amended to allow for consolidation durvalumab. The primary objective was to estimate PTC rate at 1-year with a hypothesis that the 1-year PTC rate is ≥90%. Secondary objectives were to establish the safety, feasibility, objective response rate (ORR; RECISTv1.1), and rates of regional & distant control, disease-free survival (DFS), and overall survival (OS). Exploratory functional MRI (fMRI) scans before and within the first 30 hrs of the first SBRT fraction were performed in 11 patients.The study enrolled 21 patients (10 male, 11 female), with median age 62 years (range 52-78). 16 patients received 6 Gy x 2 SBRT boost, while 5 patients received 8 Gy x 2 SBRT boost. 18 patients received C/P chemotherapy, of whom 9 patients received consolidation C/P. Six patients received consolidation durvalumab. Median pre-treatment primary tumor size was 5.0 cm (range 1.0-8.3). Median and mean follow-up were17.9 and 20.2 months, respectively. The most common toxicities were fatigue, neutropenia, leukopenia, lymphopenia, anemia, pneumonitis, fibrosis, dyspnea and esophagitis. Five grade 4 toxicities related to treatment occurred [lymphopenia (3), neutropenia (1), and leukopenia (1)], but no grade 5 toxicities related to treatment occurred. ORR at 3 and 6 months was 72.7% and 80.0%. The PTC rate was 100% and 92.3% at 1 and 2 years, respectively. The 2-year regional and distant control were 81.6% and 70.3%, respectively. Disease-free survival and overall survival at 2 yrs were 46.1% and 50.3%, respectively. Median survival was 37.8 months. fMRI detected a mean relative decrease in BOLD signal of -87.1% (P = 0.05).Dose escalation to the primary tumor utilizing upfront SBRT appears feasible and safe. PTC was high and other oncologic endpoints compared favorably with the literature. Through the use of 1 CT simulation dataset, accurate calculation of the planned dose through the 2 sequentially-delivered plans is achievable.

1180P Anlotinib combined with radiotherapy in locally advanced non-small cell lung cancer (LANSCLC): A prospective, single-arm, phase II study

The standard treatment for patients with good performance status with unresectable LANSCLC is concurrent chemoradiotherapy (CRT), The new treatment strategies of patients who could not tolerate CRT or refused chemotherapy are necessary. Anlotinib is a novel multi-target antiangiogenesis agent that inhibits VEGFR, FGFR, PDGFR, c-kit, which showed encouraging efficacy and good tolerability for advanced NSCLC in ALTER-0303 trial. Emerging clinical data suggested that antiangiogenic drugs could enhance the efficacy of radiotherapy by alleviating tumor hypoxia and improving perfusion.