Concurrent Thoracic Radiotherapy Research Articles

Radiation pneumonitis after concurrent aumolertinib and thoracic radiotherapy in EGFR-mutant non-small cell lung cancer patients

BackgroundThe superior efficacy of concurrent thoracic radiotherapy (TRT) and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has been proven in locally advanced and advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, the high incidence of radiation pneumonitis (RP) reduced by concurrent TRT and TKIs has attracted widespread attention. Thus, this study was designed to investigate the rate and risk factors for RP in EGFR-positive NSCLC patients simultaneously treated with aumolertinib and TRT. MethodsWe retrospectively evaluated stage IIIA-IVB NSCLC patients treated with concurrent aumolertinib and TRT between May 2020 and December 2022 at Shandong Cancer Hospital and Institute, Shandong, China. RP was diagnosed by two senior radiologists and then graded from 1 to 5 according to the Common Terminology Criteria for Adverse Events v5.0. All risk factors were evaluated by univariate and multivariate logistic regression analyses.ResultsA total of 49 patients were included, the incidence of grade ≥ 2 RP was 42.9%. Grade 2 and 3 RP were observed in 28.6% and 14.3% of patients, respectively. Grade 4 to 5 RP were not observed. the gross total volume (GTV) ≥ 21 ml and ipsilateral lung V20 ≥ 25% were risk factors for RP. The median progression-free survival (PFS) in the first-line therapy group and second-line therapy group were 23.5 months and 17.2 months, respectively (p = 0.10).ConclusionsBetter local control is achieved with concurrent TRT and aumolertinib, and special attention should be given to controlling ipsilateral lung V20 and GTV to reduce the risk of RP.

CRES3T: A single-arm confirmatory trial of S-1 plus cisplatin with concurrent radical-dose radiotherapy followed by surgery for superior sulcus tumor.

8514 Background: A multicenter, single-arm, confirmatory trial (CRES3T) was conducted to investigate the efficacy and safety of S-1 plus cisplatin and concurrent radical-dose thoracic radiotherapy (TRT) followed by surgery in patients with superior sulcus tumor (SST). To date, no clinical trials on radical-dose TRT in the induction setting for SST have been conducted. Methods: SST was defined as a tumor that directly invades the chest wall including the first rib or more cephalad, subclavian artery, or subclavian vein according to CT or MRI scans. Eligible patients were 20 to 75 years old and had pathologically proven non-small cell lung cancer, performance status of 0–1, and no history of prior treatment. The patients received induction therapy consisting of three cycles of S-1 plus cisplatin with concurrent TRT (66 Gy in 33 fractions) followed by surgery. S-1 was administered orally at 40 mg/m2 twice per day, on days 1–14 along with an intravenous infusion of cisplatin (60 mg/m2) on day 1. The treatment cycles were repeated every four weeks. The primary endpoint was the 3-year overall survival (OS) rate, and key secondary endpoints included progression-free survival (PFS) rate, objective response rate (ORR), pathological complete remission (pCR) rate, and toxicity. Results: Between June 2014 and March 2019, 61 patients registered and received induction therapy. Pathological diagnoses were 30 adenocarcinoma, 20 squamous cell carcinoma, and 11 others. Radiologically diagnosed tumor invasion sites were the chest wall (n=57), subclavian artery (n=18), and subclavian vein (n=10). One patient with distant metastasis that manifested after starting induction therapy was removed from this study. Forty-nine patients underwent lobectomy and resection of the involved sites. The complete resection rate was 98% (48/49). Median follow-up time was 54 months. The 3-year OS and PFS rates were 73% (95% CI: 60–83%) and 53% (95% CI: 40–65%), respectively. The ORR and pCR rate were 42% (25/60, 95% CI: 29–54%) and 33% (16/49, 95% CI: 20–46%), respectively. Grade (G) 3 or 4 toxicities during induction therapy included neutropenia (28%), anemia (13%), thrombocytopenia (5%), and hyponatremia (8%). Two (3%) cases of pneumonia resulted in death. G3 surgical complications such as supraventricular arrhythmia, chylothorax, pleural effusion, pneumonia, mediastinitis, wound infection, and arm neuropathy developed in one (2%) patient each. One (2%) cardiac arrest on postoperative day 3 resulted in death. Conclusions: CRES3T demonstrated that induction therapy using S-1 plus cisplatin and concurrent radical-dose TRT followed by surgery was safe and effective in treating SST. Therefore, this strategy is potentially a new standard treatment for SST. (UMIN: 000014386, jRCT: s031180401.). Clinical trial information: UMIN000014386 .

Final survival data from a randomized phase II trial comparing high-dose with standard-dose twice-daily (BID) thoracic radiotherapy (TRT) in limited stage small-cell lung cancer (LS SCLC).

8512 Background: Concurrent chemotherapy and TRT is standard treatment of LS SCLC. BID TRT of 45 Gy/30 fractions is the most recommended schedule. Trials report 5-year survival rates of up to 36%, illustrating that some are cured but also need for better treatment. Many treatment failures are due to relapses within TRT fields, and it has been proposed that higher TRT doses might improve local control and consequently survival. However, high-dose once-daily (QD) TRT of 66-70 Gy do not prolong survival. We investigated whether high-dose BID TRT of 60 Gy/40 fractions was tolerable and improved survival compared with the established 45 Gy schedule (NCT02041845). Primary analyses presented at ASCO 2020 showed that the trial was highly positive for the primary endpoint, 2-year survival (60 Gy: 74.2%, 45 Gy: 48.1%, OR 3.09 [95% CI 1.62-5.89]; p=0.0005). We now present updated and final survival data. Methods: Patients ≥18 years with PS 0-2, confirmed SCLC, LS according to the IASLC definition after PET CT staging received 4 courses of platinum/etoposide and were randomized to receive 60 Gy or 45 Gy to PET CT positive lesions. TRT started concurrently with the 2nd chemotherapy course. Responders were offered QD prophylactic cranial irradiation of 25-30 Gy. All patients were followed for 5 years or until death. Results: 170 eligible patients were randomized at 22 Scandinavian hospitals from 2014-2018 (60 Gy: n=89, 45 Gy: n=81). Median age was 65, 31.2% were ≥70 years, 57.1% women, 89.4% had PS 0-1, 83.5% stage III disease, 7.6% pleural effusion and 20.0% ≥5% weight loss last three months before enrollment. Baseline patient and disease characteristics and TRT planning target volumes were well balanced between treatment arms. Completion rates of chemotherapy (60 Gy: 92.1%, 45 Gy: 87.7%) and TRT (60 Gy: 96.6%, 45 Gy: 91.4%) were similar. Patients on the high-dose arm did not experience more grade 3-4 esophagitis (60 Gy: 21.2%, 45 Gy: 18.2%; p=0.83) or pneumonitis (60 Gy: 3.4%, 45 Gy: 0.0%; p=0.39), other grade 3-4 toxicity or treatment related deaths. The 60 Gy group had numerically longer PFS (median PFS 60 Gy: 18.6 months [95% CI 11.6-25.6], 45 Gy: 10.9 months [95% CI 8.7-13.2], HR 0.76 [95% CI 0.53-1.08]; p=0.13). Results for the primary endpoint remain unchanged. The higher TRT dose significantly prolonged survival (median OS 60 Gy: 43.5 months [95% CI 30.4-56.6], 45 Gy: 22.6 months [95% CI 17.2-28.0], HR 0.69 [0.48-0.99]; p=0.043) and provided higher 4.5 year survival rate (60 Gy: 41.6% [95% CI 30.4-56.6], 45 Gy: 28.4% [95% CI 18.9-39.5], OR: 1.79 [95% CI 0.95-3.41]). 5-year survival rates will be presented at the meeting. Conclusions: Compared with LS SCLC patients who received standard TRT, patients receiving high-dose BID TRT of 60 Gy did not experience more toxicity, had a substantial prolongation of survival and a much higher long term survival rate. Clinical trial information: NCT02041845 .

Preliminary results of randomized phase II study of etoposide plus lobaplatin or etoposide plus cisplatin with concurrent thoracic radiotherapy in the treatment of limited-stage small cell lung cancer.

The purpose is to compare the clinical efficacy and toxicity of etoposide plus lobaplatin (EL) or etoposide plus cisplatin (EP) with concurrent thoracic radiotherapy during the treatment of limited-stage small cell lung cancer (LS-SCLC). Forty-two patients with LS-SCLC were randomly divided into EL ( n = 19) or EP ( n = 23) regimens combined with thoracic intensity-modulated radiotherapy. The primary endpoint was 1-year progression-free survival (PFS) rate. The 1-, 2-, and 3-year PFS rates in the EL and EP cohorts were 50.8, 38.1, and 12.7%; and 56.5, 43.5, and 29.0%, respectively ( P = 0.527), whereas the 1-, 2-, and 3-year overall survival (OS) rates were 72.2, 52.5, and 43.8%; and 73.9, 48.4, and 48.4%, respectively ( P = 0.923). The hematological toxicities were similar in two cohorts. However, gastrointestinal reactions were more severe in the EP group. The incidence of nausea and vomiting in EL and EP cohorts were 31.6% vs. 73.9% ( P = 0.006) and 20.1% vs. 60.9% ( P = 0.009), respectively. The two cohorts did not show ≥grade 4 radiation esophagitis and ≥grade 3 radiation pneumonitis. The incidence of acute radiation esophagitis in EL group was lower ( P = 0.038), both groups showed a similar incidence of radiation pneumonitis ( P = 1.000). EL or EP chemotherapy with concurrent thoracic radiotherapy showed similar PFS and OS. The EL group showed milder gastrointestinal toxicity and radiation esophagitis. Radiation pneumonitis and hematological toxicity were similar in the two regimens, which can be tolerated by patients.

Dose-Limiting Pulmonary Toxicity in a Phase 1/2 Study of Radiation and Chemotherapy with Ipilimumab Followed by Nivolumab for Patients With Stage 3 Unresectable Non-Small Cell Lung Cancer

We hypothesized that concurrent ipilimumab with chemoradiationtherapy (chemoRT) followed by maintenance nivolumab would be safe for patients with unresectable stage III non-small cell lung cancer (NSCLC). We aimed to assess the safety (phase 1) and the 12-month progression-free survival (PFS) (phase 2) in a multi-institution prospective trial. Eligible patients had unresectable stage III NSCLC. The treatment included platinum doublet chemotherapy with concurrent thoracic radiation therapy to 60 Gy in 30 fractions and ipilimumab (1 mg/kg) delivered during weeks 1 and 4. After chemoRT, maintenance nivolumab (480 mg) was given every 4 weeks for up to 12 cycles. Adverse events (AEs) were assessed according to the Common Terminology Criteria for Adverse Events, version 5.0. Survival analyses were performed with Kaplan Meier (KM) methods and log-rank tests. The trial was discontinued early after enrolling 19 patients without proceeding to the phase 2 component because of unacceptable toxicity. Sixteen patients (84%) had grade ≥3 (G3+) possible treatment-related toxicity, most commonly pulmonary AEs (n=8, 42%). Fourteen patients (74%) discontinued study therapy early because of AEs (n=12, 63%) or patient choice (n=2, 11%). Eleven patients (58%) experienced G2+ pulmonary toxicity with median time to onset 4.1 months (95% CI 2.6-not reached [NR]), and 12-month freedom from G2+ pulmonary toxicity 37% (95% CI, 16-59). Five patients had G5 AEs, including 3 with G5 pulmonary AEs (1 respiratory failure with pneumonitis and pulmonary embolism, 1 pneumonia/chronic obstructive pulmonary disease exacerbation, 1 pulmonary fibrosis). Despite toxicities, the median PFS was 19.2 months (95% CI 6.1-NR) and the median overall survival was NR (95% CI 6.1-NR) with median follow-up of 30.1 months by the reverse KM method. Concurrent ipilimumab with chemoRT for unresectable stage III NSCLC is associated with pulmonary toxicity that may limit opportunities for improved outcomes. Future studies aiming to incorporate ipilimumab or other anti-CTLA4 therapies into management of unresectable stage III NSCLC should consider careful measures to minimize toxicity risk.

Cardiac toxicity in patients with lung cancer receiving thoracic radiotherapy and immunotherapy.

Immune checkpoint inhibitors (ICIs) are used to treat locally-advanced and metastatic lung cancer, which can lead to severe immunogenic-related cardiotoxicities. We assessed the risk of cardiotoxicity in ICI-treated lung cancer patients with or without cardiac radiation from thoracic radiotherapy. Retrospective data was collected on Stage III-IV lung cancer patients who received ICIs between 2015 and 2018. All cardiotoxicities associated with ICI were assessed in correlation with the timing of radiotherapy (RT) in relation to ICI, and the mean RT heart dose. The rate of cardiac events in relation to RT timing and heart dose was compared using multiple logistic regression including the Framingham risk score and steroid use prior to ICI therapy. Of 194 ICI-treated patients evaluated, 55.2% (n=107/194) patients had received thoracic RT at a median dose of 60.4 Gy (range, 15-75). Cardiotoxicities such as non-ST elevated myocardial infarction and new onset supraventricular tachycardias were observed in 13 (12.2%) of those who had thoracic RT versus 9 (10.3%) who did not (p=0.87). 38 patients who received RT concurrently with ICI did not develop any cardiotoxicity whereas 14.1% (n=22/156) of those who did not receive concurrent RT developed cardiotoxicities (univariate, p=0.030; multivariate, p=0.055). There were no significant differences in the mean heart RT dose, Framingham risk score, and steroid treatment between patients that received concurrent RT with ICI versus non-concurrent RT/ICI. ICI-related cardiotoxicities were not significantly associated with patients who received concurrent thoracic radiotherapy in this retrospective review. Further validation of prospective studies is needed to confirm these results.

308P Phase II study of S-1 and cisplatin with concurrent thoracic radiotherapy followed by durvalumab for unresectable, locally advanced non-small cell lung cancer in Japan (SAMURAI study)

The standard of treatment for patients with unresectable, locally advanced NSCLC (LA-NSCLC) is chemoradiotherapy (CRT) followed by durvalumab. Although phase II studies in Japan have shown high efficacy and good tolerability of CRT with cisplatin + S-1 (SP), no prospective study using durvalumab after SP-based CRT has been reported. Thus, we conducted a phase II study using durvalumab after SP-based CRT for LA-NSCLC. The primary analysis was already presented in IASLC Asia 2022. Here, we report the additional results.

Incidence of Radiation Pneumonitis Among Patients Treated with Concurrent Thoracic Radiotherapy and Osimertinib for Metastatic Non-Small Cell Lung Cancer

<h3>Purpose/Objective(s)</h3> A case series from China published in 2020 reported a high rate of radiation pneumonitis (RP) among 11 patients treated with concurrent thoracic radiotherapy (TRT) and osimertinib, including 9% who developed a fatal complication. We analyzed the RP rates for patients at our institution who were also treated with a similar combination for metastatic non-small cell lung cancer (NSCLC). <h3>Materials/Methods</h3> This retrospective study was performed at a single academic medical center in the US. We identified all patients who were treated with concurrent TRT and osimertinib between June 2016 and December 2021. Baseline patient characteristics, tumor size and location, and dosimetric parameters were evaluated. The highest grade of RP that developed within 6 months of treatment was scored in accordance with CTCAE v5.0. Fisher's exact test and logistic regression were performed to investigate the association of pre-treatment factors with development of grade ≥2 and grade ≥3 RP. <h3>Results</h3> Sixteen patients with metastatic NSCLC were treated with concurrent TRT and osimertinib over the study time period. The treatment site of each patient's pulmonary metastases was as follows: peripheral in 4 (25%), central in 4 (25%) (within 1-2 cm of the proximal bronchial tree [PBT]), ultra-central in 7 (44%) (within 1 cm of the PBT), and mediastinal in 1 (6%). Two of 16 patients withheld osimertinib 24-48 hours before and after TRT, both of which had tumors in an ultra-central location. Patients were treated with a median dose of 50 Gy (11-65 Gy) in a median of 7.5 fractions (1-15 fractions); the median duration of TRT was 10 days (1-22 days). The median follow-up time was 13 months (1 – 61 months). Nine patients developed grade ≥2 RP (56%) with a median time to onset of 29 days (1-84 days). The severity of RP was grade ≥3 in 6 (37.5%) and grade 4 in 1 (6.3%); no patients had grade 5 RP. Of the 6 patients who developed grade ≥3 RP, 2 (33.3%) were treated with stereotactic body radiotherapy (SBRT) while 4 (66.6%) were treated with hypofractionated TRT. All patients who developed grade ≥3 RP were female. Tumor location for patients who developed grade ≥3 RP was central in 3 (50%), ultra-central in 2 (33%) and mediastinal in 1 (17%); no patients with peripheral tumors developed grade ≥3 RP. Both patients who withheld osimertinib before and after TRT did not develop RP. The association of female sex and non-peripheral tumor location with grade ≥3 RP was not statistically significant in the context of a small case series (p=0.23). RP was not associated with the use of SBRT vs hypofractionated TRT or mean lung dose. <h3>Conclusion</h3> TRT with concurrent osimertinib was associated with a high rate of RP, particularly when the site of pulmonary metastases was in a central, ultra-central, or mediastinal location. Withholding osimertinib 24-48 hours before and after TRT may mitigate this risk. These data raise safety concerns that are not currently listed in treatment guidelines. Further research is indicated to validate these findings in larger cohorts.

Observation of Acute Toxicity Events in Lung Cancer Patients Treated Concurrently with a Tyrosine Kinase Inhibitor

<h3>Purpose/Objective(s)</h3> Available tyrosine kinase inhibitors (TKI) for patients with non-small-cell lung cancer (NSCLC) have long half-lives. If thoracic radiation is given, it can be impractical to hold the TKI long enough for a washout. We set out to determine whether patients taking a TKI are at elevated risk for acute esophageal, pulmonary, or cardiac toxicity following thoracic radiation. <h3>Materials/Methods</h3> We performed a single-institution retrospective study of patients who had lung radiation from March 2011 to December 2021. Concurrent TKI use was defined as drug use within 3 months before or after radiation. Patients completed palliative or definitive thoracic radiation courses (including SBRT) for any primary lung cancer. Radiation doses and dosimetric parameters (esophagus mean and V30, heart mean and V25, lung mean and V20) were converted to biologically effective doses (BED₁₀) using an a/b ratio of 10 Gy. CTCAE acute toxicity outcomes were determined within 12 months of completion of radiation and compared using chi-square tests, Fisher's exact tests, and multivariate logistic regressions. <h3>Results</h3> A total of 105 patients receiving lung radiation were identified with median follow up of 12 months (range 0.6–114 months). Histologies included adenocarcinoma (51.4%), squamous cell carcinoma (23.8%), other NSCLC (15.2%), and SCLC (9.5%). 33 patients (31.4%) had metastatic disease at the time of radiation treatment. Median dose was 72 BED₁₀ Gy (range 15.7 to 151.2 BED₁₀ Gy). A total of 14.3% (n=15/105) of patients received concurrent TKI. The rate of grade 2-3 acute esophagitis was 20.0% (18/90) and 53.3% (8/15) for patients receiving radiotherapy without and with concurrent TKI, respectively (p = 0.006). There were no grade 4-5 esophagitis events. When controlling for mean esophageal dose and concurrent chemotherapy, concurrent TKI use was found to be an independent predictor for grade 2-3 esophagitis (OR = 6.91, 95% CI = 1.99 – 26.03, p = 0.003). Acute esophagitis was most frequently seen with osimertinib (4/7 = 57.1%), lorlatinib (2/2 = 100.0%), and crizotinib (2/3 = 67.7%). The rate of grade 2-3 pneumonitis was 5.6% (5/90) and 15.3% (2/13) without and with concurrent TKI, respectively (p = 0.261). On multivariate analysis, TKI use was not associated with pneumonitis. There were no acute grade 4-5 pneumonitis events or grade 2-5 cardiac toxicities. <h3>Conclusion</h3> This study raises the hypothesis that acute esophageal toxicity may be higher after radiation for patients receiving many of the most common TKIs. Thoracic radiation plays a crucial role in the management of NSCLC, and as the use of TKIs expands, it is critical to quickly identify potential complications associated with concurrent thoracic radiation.

Evaluation of Pneumonitis in EGFR-Mutated Non-Small Cell Lung Cancer Patients Receiving Osimertinib and Thoracic Radiotherapy

<h3>Purpose/Objective(s)</h3> In epidermal growth factor receptor mutated (EGFR+) metastatic non-small cell lung cancer (mNSCLC), pneumonitis is a known side effect independently associated with both Osimertinib and thoracic radiotherapy (TRT). The objective of this study was to examine the relationship between concurrent Osimertinib and TRT with regards to pneumonitis, and to observe patterns of practice regarding the cessation of Osimertinib during TRT. <h3>Materials/Methods</h3> In this single institution retrospective cohort study between 2016 and 2020, patients with EGFR+ mNSCLC who received both Osimertinib and TRT were included. TRT was defined as any course of radiotherapy that involved lung parenchyma within the treated field. The primary endpoint was the incidence of symptomatic (CTCAE grade ≥ 2) pneumonitis. Comparisons were made with multivariable Cox proportional hazards regression for both grade ≥ 2 and any grade pneumonitis. <h3>Results</h3> Of the 151 patients receiving Osimertinib during the study period, 41 underwent 147 courses of radiation either during or within 6 months of Osimertinib initiation, with 68 (46.3%) lesions treated with TRT. In total, 5 patients developed RT-related symptomatic pneumonitis (12.2%), of which 1 was grade 4 and another grade 5. Mean (±SD) age at TRT was 65.5 (±12.0) years. Most patients had de novo metastatic disease (n=31; 75.6%), adenocarcinoma histology (n=38; 92.7%), and 16 (39%) were on Osimertinib as first line systemic therapy. The mean (±SD) number of cycles of Osimertinib was 9.6 (±4.3). Median total dose and fractionations were 20 Gy (interquartile range [IQR]: 20-30 Gy) and 5 (IQR: 1-5), respectively. During TRT, Osimertinib was knowingly held in 12 patients (29.3%), most commonly for 1-2 days before and after (n=7; 17.1%) the course of treatment. Osimertinib was knowingly continued during TRT for 5 patients (12.2%), and in 8 patients (19.5%) it was not documented whether the medication was held. Multivariable analysis identified that each additional cycle of Osimertinib was associated with an increased incidence of grade ≥ 2 pneumonitis (hazard ratio [HR]: 1.54, 95% confidence interval [CI]: 1.15-2.07, p=0.004). Total radiation dose was also associated with increased incidence of any grade of pneumonitis (HR per 5 Gy: 1.38, 95% CI: 1.03-1.86, p=0.031). There was no association with incidence of pneumonitis (any grade) if Osimertinib was continued during TRT (HR: 3.36, 95% CI: 0.13-86.56, p=0.47) or if TRT was given within 6 months of Osimertinib initiation (HR: 0.20, 95% CI: 0.02-2.21, p=0.19). <h3>Conclusion</h3> In patients with EGFR+ mNSCLC treated with Osimertinib and TRT, the risk of symptomatic pneumonitis was moderate, and in 2 instances serious. Patterns on whether to hold Osimertinib during TRT, and for how long, were variable. Symptomatic pneumonitis with TRT was associated with prolonged Osimertinib use. Further research is required to further clarify the safety of the combination of these two treatment modalities.

Risk Factors of Treatment-Related Pneumonitis after Thoracic Radiotherapy/Chemoradiotherapy Combined with Anti-PD-1 mAb in Esophageal Squamous Cell Carcinoma

<h3>Purpose/Objective(s)</h3> Treatment-related pneumonitis (TRP) and radiation recall pneumonitis (RRP) has recently been identified as a toxicity triggered by thoracic irradiation combined with anti-PD-1 mAb in esophageal squamous cell carcinoma (ESCC). However, the incidence, risk factors and dose-volume parameters remain unknown. <h3>Materials/Methods</h3> We analyzed 97 patients with ESCC who received thoracic radiotherapy/chemoradiotherapy combined with anti-PD-1 mAb. There were 74 patients of newly diagnosed/locally advanced unresectable esophageal cancer, 22 patients of recurrent after radical resection /metastatic esophagus cancer, and 1 patient of resectable esophageal cancer with neoadjuvant therapy. 41 patients received concurrent thoracic radiotherapy and anti-PD-1 mAb, 56 patients received sequential thoracic radiotherapy and anti-PD-1 mAb. The median radiation dose of PTV was 59.4Gy (range from 45Gy to 66Gy, 1.8Gy-2.2Gy per fraction). TRP and RRP were classified according to the CTCAE version 5.0 and the effect of dose-volume parameters of lung on TRP and RRP was analyzed. <h3>Results</h3> The average value of V_5, V_10, V_20, V₃₀ and MLD of lung was 49.2% (27.9%-73.6%), 35.9% (21.7%-48.6%), 21.3% (12.7%-29.9%), (1.5% -17.5%) and 1092.5cGy (666.9cGy-1569.6cGy), respectively. The incidence of TRP was 46.4% (45/97). 41.2% of patients developed grade 1 or 2 pneumonitis and 4.1% of patients was grade 3 pneumonitis. Of note, there was 1 death probably related with TRP. The incidence of RRP was 14.4% (14/97). 14.4% of patients developed grade 1 or 2 pneumonitis and there was no grade ≥3 RRP. The median onset time of TRP and RRP was 16 weeks after receiving anti-PD-1 mAb (2.6 weeks-65.9 weeks) and 48.9 weeks (27 weeks-91.1 weeks) after thoracic radiotherapy, respectively. Result of multivariate analysis showed that V₅ was an independent risk factor of grade ≥2 TRP (P=0.003, OR=1.106). The incidence of grade ≥2 TRP in the V₅≥55.7% group was significantly higher than that in the V₅<55.7% group (56.5% vs 16.2%). There was only a trend towards higher V₅, V₃₀, V₃₅, and MLD related to RRP without statistical significance. <h3>Conclusion</h3> We demonstrate a high risk of TRP in ESCC patients receiving thoracic radiotherapy/chemoradiotherapy combined with anti-PD-1 mAb and mostly pneumonitis was grade 1 and grade 2. While the occurrence of RRP is relatively less and the severity is mild. TRP (grade≥2) is associated with V₅≥55.7%, so clinicians should pay more attention to restriction of V₅ and V₅<55.7% might be a safer volume. Therapy strategy combined thoracic radiotherapy/chemoradiotherapy with anti-PD-1 mAb might be a safe choice, it is worth a further exploration.

EP08.05-001 Evaluation of Pneumonitis in EGFR-Mutated Non-Small Cell Lung Cancer Patients Receiving Osimertinib and Thoracic Radiation

Osimertinib and thoracic radiotherapy (TRT) are established therapies for epidermal growth factor receptor mutated (EGFR+) metastatic non-small cell lung cancer (mNSCLC). However, pneumonitis is a known side effect independently associated with both treatment modalities. The objective of this study was to examine the impact of concurrent Osimertinib and TRT on the incidence of pneumonitis, and to observe patterns of practice regarding the cessation of Osimertinib during TRT.

P28-14 Long-term response to alectinib in a patient with ALK-fusion gene emerged in afatinib-resistant EGFR-mutated lung cancer

When a 71-year-old man developed right putamen hemorrhage, a mass lesion in left lung apex with enlarged mediastinal lymph nodes on CT was detected. A CT-guided biopsy specimen revealed adenocarcinoma with EGFR exon 19 deletion without ALK fusion gene. He was a current smoker (125 pack-year) and performance status was 1. We planned surgery following concurrent thoracic radiation with chemotherapy (cisplatin plus docetaxel) for stage IIIA (cT1bN2M0) non-small cell lung cancer. However, lobectomy could not be performed because pleural dissemination was observed at chest surgery.

A phase II study of S-1 and cisplatin with concurrent thoracic radiotherapy followed by durvalumab for unresectable, locally advanced non-small-cell lung cancer in Japan (SAMURAI study): primary analysis.

The standard of care for unresectable, locally advanced non-small-cell lung cancer (LA-NSCLC) is chemoradiotherapy (CRT) followed by durvalumab, based on the PACIFIC study. Although multiple Japanese phase II studies have shown high efficacy and tolerability of CRT with cisplatin plus S-1 (SP), no prospective study using durvalumab after SP-based CRT has been reported. We conducted a multicenter phase II study of this approach, the interim analysis of which showed a high transition rate to durvalumab consolidation therapy. Here, we report the primary analysis results. In treatment-naïve LA-NSCLC, cisplatin (60 mg/m2, day 1) and S-1 (80-120 mg/body, days 1-14) were administered with two 4-week cycles with concurrent thoracic radiotherapy (60 Gy) followed by durvalumab (10 mg/kg) every 2 weeks for up to 1 year. The primary endpoint was 1-year progression-free survival (PFS). The expected 1-year PFS and its lower limit of the 80% confidence interval (CI) were set as 63% and 47%, respectively, based on the results of TORG1018 study. In all, 59 patients were enrolled, with 51 (86.4%) proceeding to durvalumab. The objective response rate throughout the study was 72.9% (95% CI: 59.7-83.6%). After median follow-up of 21.9 months, neither median PFS nor OS was reached. The 1-year PFS was 72.5% (80% CI: 64.2-79.2%, 95% CI: 59.1-82.2%), while the 1-year overall survival was 91.5% (95% CI: 80.8-96.4%). No grade 5 adverse events were observed throughout the study. The most common adverse event during the consolidation phase was pneumonitis (any grade, 78.4%; grade ⩾3, 2.0%). Eventually, 52.5% of patients completed 1-year durvalumab consolidation therapy from CRT initiation. This study of durvalumab after SP-based CRT met its primary endpoint and found a 1-year PFS of 73% from CRT initiation. This study provides the first prospective data on the prognosis and tolerability of durvalumab consolidation from the initiation of CRT. Japan Registry of Clinical Trials, jRCTs031190127, registered 1 November, 2019, https://jrct.niph.go.jp/latest-detail/jRCTs031190127.

Prospective analysis of factors precluding the initiation of durvalumab from an interim analysis of a phase II trial of S-1 and cisplatin with concurrent thoracic radiotherapy followed by durvalumab for unresectable, locally advanced non-small cell lung cancer in Japan (SAMURAI study).

Background:The standard of care for unresectable, locally advanced non-small cell lung cancer (LA-NSCLC) is chemoradiotherapy (CRT) followed by durvalumab, based on the PACIFIC trial. Disease progression and pneumonitis were reported as the main reasons to preclude the initiation of durvalumab in multiple retrospective studies. However, the transition rate and the reasons for failure to proceed to consolidation therapy with durvalumab after CRT were not evaluated prospectively. Although phase II studies in Japan have shown high efficacy and tolerability of CRT with cisplatin + S-1 (SP), no prospective study using durvalumab after SP-based CRT has yet been reported. We therefore conducted a phase II study to verify the efficacy and safety of durvalumab following SP-based CRT. In this interim analysis, we report the transition rate and the reasons for its failure.Methods:In treatment-naïve LA-NSCLC, cisplatin (60 mg/m2, day 1) and S-1 (80–120 mg/body, days 1–14) were administered with two 4-week cycles with concurrent thoracic radiotherapy (60 Gy) followed by durvalumab every 2 weeks for up to 12 months. The primary endpoint was 12 month progression-free survival rate.Results:Fifty-nine patients were enrolled, of whom 86.4% (51/59) proceeded to durvalumab. All of them initiated durvalumab within 42 days after CRT [median 18 days (range: 3–38)], including 27.5% (14/51) in <14 days. Common reasons for failure to proceed to durvalumab were disease progression (2/59, 3.4%) and adverse events (6/59, 10.2%). Among the latter cases, four resumed treatment and proceeded to durvalumab within 42 days on off-protocol. The objective response rate and the disease control rate were 62.7% and 93.2%, respectively. The incidences of ⩾grade 3 pneumonitis, febrile neutropenia, and esophagitis were 0%, 8.5%, and 3.4%, respectively.Conclusion:Regarding durvalumab after CRT, this interim analysis of the SAMURAI study clarified the high transition rate, early introduction, and reasons for failure to proceed to consolidation therapy, which were not determined in the PACIFIC trial.Trial registration:Japan Registry of Clinical Trials, jRCTs031190127, registered 1 November, 2019, https://jrct.niph.go.jp/latest-detail/jRCTs031190127.

Randomized phase II trial of pemetrexed-cisplatin plus bevacizumab or thoracic radiotherapy followed by surgery for stage IIIA (N2) nonsquamous non–small cell lung cancer

BackgroundPersonalized Induction Therapy-1 is a multicenter, randomized phase II selection design trial of the efficacy and safety of platinum-doublet induction chemotherapy plus angiogenesis inhibitors/concurrent thoracic radiotherapy (TRT) followed by surgery for stage IIIA (N2) nonsquamous non–small cell lung cancer (NSCLC). MethodsPatients with pathologically proven stage IIIA (N2) nonsquamous NSCLC were assigned at random to 1 of 2 arms. Patients received (1:1) induction therapy with pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 plus bevacizumab 15 mg/kg intravenously every 3 weeks for 3 cycles (bevacizumab arm) or concurrent TRT (45 Gy in 25 fractions; TRT arm) before surgery. The primary endpoint was the 2-year progression-free survival (PFS) rate. ResultsEighty-two patients were treated, including 42 in the bevacizumab arm and 40 in the TRT arm. Thirty-eight patients (90%) in the bevacizumab arm and 37 patients (93%) in the TRT arm underwent surgery. The objective response rates in the 2 groups were 50% and 60%, respectively (P = .36). The 2-year PFS and overall survival rates were 37% (95% confidence interval [CI], 22.4%-51.2%) and 50% (95% CI, 33.8%-64.2%) (hazard ratio [HR], 1.34; P = .28), respectively, and 81% (95% CI, 64.7%-89.7%) and 80% (95% CI, 64.0%-89.5%) (HR, 1.10; P = .83), respectively. Although grade 5 toxicity did not occur during induction therapy, 2 patients in the bevacizumab arm died due to bronchopleural fistula. ConclusionsAlthough not significant, the 2-year PFS rate was higher in the TRT arm than in the bevacizumab arm. Fatal surgical complications were observed only in the bevacizumab arm. Therefore, pemetrexed-cisplatin with concurrent TRT was chosen as the investigational induction treatment strategy for future phase III trials.

Cardiotoxicity in Patients With Lung Cancer Receiving Thoracic Radiotherapy and Immune-Checkpoint Therapy

Immune checkpoint inhibitors (ICIs) have been widely adapted as part of the treatment of locally advance and metastatic lung cancer. ICIs can lead to severe immunogenic related cardiotoxicities, however, the overall cardiotoxic profile of these agents when combined with thoracic radiation therapy is not well defined. Here, we assessed the risk of cardiotoxicity in ICI-treated lung cancer patients with or without cardiac radiation from thoracic radiotherapy.Retrospective data was collected on Stage III-IV small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) patients who received ICIs between 2015 and 2018 at a large academic tertiary care hospital. All cardiotoxicities associated with ICI were assessed by a cardiologist and in correlation with history of thoracic radiotherapy (RT), the timing of RT in relation to ICI, and the mean RT heart dose. Multivariate analysis was performed on multiple logistic regression including the Framingham risk score and steroid use during the ICI therapy.Of 194 ICI-treated patients evaluated, 66 (34.02%) and 128 (65.98%) had Stage III and IV SCLC or NSCLC, respectively, the median age was 64 years (range, 36-88), and 42.47% were female. Within the total cohort, 55.2% (n = 107/194) patients had received thoracic RT at a median dose of 60.4 Gy (range, 15-75). Cardiotoxicities such as non-ST elevated myocardial infarction and new onset supraventricular tachycardias were observed in 13 (12.2%) of those who had thoracic RT versus 9 (10.3%) who did not (P = 0.87). There were 38 patients who received RT concurrently with ICI and did not develop any cardiotoxicity whereas cardiotoxicity was observed in 14.1% (n = 22/156) of those who did not receive concurrent RT (univariate, P = 0.030; multivariate, P = 0.055). There were no significant differences in the mean heart RT dose, Framingham risk score, and steroid treatment between patients that received concurrent RT with ICI versus non-concurrent RT/ICI.ICI-related cardiotoxicities were not significantly associated with patients who received concurrent thoracic radiotherapy. Univariate analysis suggests a potential cardioprotective effect of thoracic RT with ICI's, which may be due to modulation of the immune response through reduction of lymphocytes involved in autoimmune processes. A larger cohort study will be conducted to further evaluate this potential cardioprotective effect.

Gefitinib With Concurrent Thoracic Radiotherapy in Unresectable Locally Advanced NSCLC With EGFR Mutation; West Japan Oncology Group 6911L

IntroductionAbout 10% of patients with locally advanced NSCLC (LA-NSCLC) harbor EGFR mutation and recent reports suggested the declined benefit with an immune checkpoint inhibitor in this population. The attempt that introduces EGFR tyrosine kinase inhibitor into the treatment of LA-NSCLC with EGFR mutation has been warranted. MethodsChemotherapy-naive patients with unresectable LA-NSCLC with sensitive EGFR mutation (exon 19 deletion or exon 21 L858R point mutation) were enrolled. Patients were treated with gefitinib (250 mg/d for 2 y) plus concurrent thoracic radiotherapy (64 Gy/32 fractions). The primary end point was progression-free survival (PFS) at 2 years (trial identifier, UMIN000008366). ResultsBetween August 2012 and November 2017, a total of 28 patients were enrolled and 27 were eligible. The median age was 67 years (range: 45–74); never/current or former smoker in 15/12 patients, respectively; Eastern Cooperative Oncology Group performance status of 0/1 in 19/8; EGFR exon 19 deletion/exon 21 L858R in 13/14; and c-stage IIIA/IIIB in 14/13. The PFS rate at 2 years by independent review was 29.6% (one-sided 95% confidence interval [CI]: 17.6%–). The overall response rate was 81.5% (95% CI: 63.3%–91.3%), median PFS was 18.6 months (95% CI: 12.0–24.5 mo), and median overall survival was 61.1 months (95% CI: 38.1 mo–not reached). Approximately half of the patients exhibited solitary brain metastasis as their first site of relapse. Adverse events greater than or equal to grade 3 were fatigue, skin reaction, and appetite loss (3.7% each). ConclusionsThis prospective study revealed the tolerability and the possible efficacy of gefitinib plus concurrent thoracic radiotherapy in patients with LA-NSCLC having EGFR mutation.

PIT-2: A multicenter phase II trail of S-1 plus cisplatin with concurrent radiotherapy followed by surgery in stage IIIA (N2) lung squamous cell carcinoma.

8543 Background: A multicenter phase II study, PIT-2 (Personized Induction Therapy-2), was performed to investigate the efficacy and safety of S-1 plus cisplatin and concurrent thoracic radiation therapy (TRT) followed by surgery in patients with stage IIIA (N2) lung squamous cell carcinoma (LSCC). To date, no clinical trials on the use of induction therapy prior to surgery have focused solely on the treatment of N2 LSCC. Methods: Eligible patients were 20 to 75 years old and had stage IIIA (pathologically proven N2) LSCC, performance status of 0-1, and no prior treatment. The patients received induction therapy consisting of three cycles of S-1 and cisplatin plus concurrent TRT (45 Gy in 25 fractions) followed by surgery. S-1 was administered orally at 40 mg/m2 twice per day, on days 1 through 14 along with an intravenous infusion of cisplatin (60 mg/m2) on day 1. The treatment cycles were repeated every four weeks. The primary endpoint was 2-year progression-free survival (PFS) rate and key secondary endpoints included overall survival (OS), the objective response rate (ORR) as defined by the Response Evaluation Criteria in Solid Tumors version 1.1, pathological complete remission (pCR) rate, feasibility, and toxicity. Results: Of the 45 patients registered between December 2013 and September 2018, 43 received induction therapy. Of the 43 patients, 39 (91%) underwent surgery (25 lobectomies, 10 bilobectomies, three pneumonectomies, and one wedge resection). The complete resection rate was 95% (37/39). Median follow-up time was 35.7 months. The 2-year PFS and OS rates were 67% (90% CI: 54-78%) and 70% (95% CI: 53-81%), respectively. The ORR and pCR rates were 86% (37/43, 95% CI: 76-96%) and 39% (15/39, 95% CI: 23-54%), respectively. Grade (G) 3 or 4 toxicities during the induction therapy in 43 patients included neutropenia (40%), anemia (9%), thrombocytopenia (7%), and hyponatremia (7%). Severe surgical complications in 39 patients included G3/4 pneumonia (5%), G3 bronchopleural fistula (5%), and G3 pleural effusion (5%). No G3/4 intraoperative adverse events occurred. There was no 30-day postoperative mortality and one 90-day postoperative mortality in a patient who underwent right pneumonectomy and developed pneumonia after discharge. Conclusions: Induction therapy using S-1 plus cisplatin and concurrent TRT followed by surgery is a promising treatment for patients with stage IIIA (N2) LSCC. Clinical trial information: 000012413.

Factors associated with survival in small cell lung cancer: an analysis of real-world national audit, chemotherapy and radiotherapy data.

The mainstay of treatment for small cell lung cancer (SCLC) involves platinum doublet chemotherapy but the optimal duration, 4 vs. 6 cycles, is not known. Concurrent thoracic radiotherapy followed by prophylactic cranial irradiation (PCI) is recommended for fit individuals with limited stage. However, outside of clinical trials, the efficacy of sequential thoracic radiotherapy and PCI for extensive stage is uncertain. This retrospective, observational, cohort study used English national lung cancer data to determine the factors associated with survival for all people diagnosed with SCLC. More precisely, for individuals who received chemotherapy, we examined survival by the chemotherapy duration, thoracic radiotherapy dose and the use of PCI. In total 6,438 people were diagnosed with SCLC. We identified that male sex (OR 0.7; 95% CI: 0.62-0.80), increasing age (P=0.01) greater comorbidity (P≤0.01), extensive stage (OR 0.21; 95% CI: 0.19-0.25) and worse performance status (PS2 vs. PS0 adjusted OR 0.38 95% CI: 0.31-0.48) were associated with reduced 1-year survival. Receipt of chemotherapy augmented survival. We analysed data for 1,761 people who had received chemotherapy. Thoracic radiotherapy (≥30 Gy for extensive stage and ≥40 Gy for limited stage) and PCI were independently associated with better survival (P≤0.01 for each), but 6 cycles of chemotherapy instead of 4 was not (limited stage adjusted OR 0.97; 95% CI: 0.48-1.97) extensive stage adjusted OR 1.34; 95% CI: 0.81-2.21). Extending chemotherapy beyond 4 cycles to 6 does not augment survival. Appropriately prescribed thoracic radiotherapy and PCI can prolong survival in both limited and extensive stage SCLC.