Here we report surgical and clinical outcomes in the Phase II LCMC3 (NCT02927301) study evaluating pre-operative treatment with atezolizumab (anti-PD-L1) in untreated stage IB-IIIB resectable NSCLC. Patients with stage IB-IIIB resectable NSCLC and ECOG PS 0/1 were eligible. Patients received neoadjuvant atezolizumab 1200 mg intravenously q3w for ≤2 cycles (days 1 and 22) followed by resection (day 40±10). Patients deemed to have benefit continued on adjuvant atezolizumab for ≤12 months. The primary endpoint was major pathological response (MPR; ≤10% viable tumor cells at surgery) in patients without EGFR/ALK+ mutations. Pre- and post-treatment positron emission tomography/computed tomography scans, pulmonary function tests and biospecimens were obtained. For safety analyses, adverse events (AEs) were classified as treatment-related (TRAE) or immune-related (irAE) and as pre-operative or post-operative (AE onset on or after date of surgery). Follow-up data from post-surgery visit were analyzed for all enrolled and dosed patients with NSCLC (N=181). Baseline characteristics were: mean age, 65.1 years; female, 93/181 (51%); current smoker, 35/181 (19%); nonsquamous histology, 112/181 (62%); and clinical stages IB (n=16), IIA (n=20), IIB (n=60), IIIA (n=71) and IIIB (n=14). In patients without EGFR/ALK mutations who underwent surgery, the MPR rate was 20% (30/147; 95% CI: 14%-28%) and the pathological complete response rate was 7% (10/147; 95% CI: 3%-12%) (see Carbone, WCLC 2020). Surgical and clinical outcomes and perioperative AEs are in the Table. Following atezolizumab, unresectability was detected pre-operatively in 22/181 (12%) and intra-operatively in 7/159 (4%). The majority of patients (151/159; 95%) had anatomic resections; only 15/101 (15%) converted to thoracotomy. Pathologic downstaging was seen in 57/181 (31%). Only 19/159 (12%) had surgery outside of protocol window. Intraoperative complications were rare (5/159; 3%). 145/159 (91%) had complete (R0) resection. Postoperative TRAEs and irAEs correlated with fewer viable tumor cells in the resected specimen (both P<0.05; Table). 30- and 30-to-90-day mortality were each 1/159 (0.6%). DFS and OS at 1 year and 18 months will be presented. Neoadjuvant atezolizumab in resectable stage IB-IIIB NSCLC was well tolerated, with no safety concerns. The 20% MPR rate successfully met the primary study objective and was comparable to that with neoadjuvant cisplatin-based therapy. Following neoadjuvant atezolizumab, resection was performed (1) safely with low perioperative morbidity and mortality, (2) infrequently outside of the protocol window and (3) with high complete resection rates.Tabled 1Enrolled and Dosed Patients With NSCLC (N = 181)Clinical vs pathological stagingPre-treatment cStagePost-treatment pStageypT0N0M008 (4)IA106 (3)IA207 (4)IA308 (4)IB16 (9)15 (8)IIA20 (11)11 (6)IIB60 (33)42 (23)IIIA71 (39)48 (27)IIIB14 (8)8 (4)IVA02 (1)Missing–4 (2)No surgery–22 (12)Patients downstaged following atezolizumab, n (%)57 (31)Timing of treatment and surgeryMedian time from screening to first dose (range), days15 (0-82)Median time from enrolment to first dose (range), days12 (1-82)Median time from last cycle to surgical resection (range), days (n = 159)21 (10-73)SurgeryStagePre-operative unresectableUnderwent surgeryIntra-operative unresectableAll, n (%)22 (12)159 (88)7 (4)IA, n1190IB, n1150IIB, n8521IIIA, n10613IIIB, n2123Patients with disease progression per RECIST while on therapy and had surgery, n (%)4 (2)Patients with disease progression per RECIST while on therapy and did not have surgery, n (%)9 (5)Patients with surgery outside 10-day window, n (%)19 (12)Stage IA, n2Stage IB, n1Stage IIB, n9Stage IIIA, n5Stage IIIB, n2Median time outside window (range), days8 (1-45)Extent of resection (n = 159)n (%)Pneumonectomy14 (9)Bilobectomy10 (6)Lobectomy125 (79)Segmentectomy2 (1)Wedge3 (2)Other5 (3)MortalityDeaths before planned surgery, n (%)a0Deaths ≤ 30 days after surgery, n (%)1b (0.6)Deaths between > 30 and ≤ 90 days after surgery, n (%)1c (0.6)HospitalizationMedian length of hospitalization (range), days (n = 48)7.5 (2-68)Intra-operative events (post hoc descriptive analysis)Bronchial complications, n (%)1 (1)Vascular complications, n (%)4 (3)Lymphadenopathy, n (%)46 (29)Peripheral adhesions, n (%)43 (27)Peri-hilar/lobar adhesions, n (%)42 (26)PathologyCompleteness of resection, n (%)R0145 (91)R17 (4)R27 (4)TRAEPre-operative (n = 181)Post-operative (n = 159)Any TRAE, n (%)101 (56)57 (36)Grade 3-49 (5)20 (13)Grade 501 (1)irAEPre-operative (n = 181)Post-operative (n = 159)Any irAE, n (%)44 (24.3)43 (27.0)Grade 3-44 (2.2)12 (8)Grade 501 (0.6)cStage, clinical stage; pStage, pathological stage; VAT, video-assisted thoracic surgery. a Planned to occur on Day 40 ± 10 of the study. b Due to sudden death, not otherwise specified. c Due to pneumonitis, deemed related to atezolizumab. Open table in a new tab

The role of immune checkpoint inhibitors in resectable NSCLC remains undefined. We report the updated safety results of the first multicenter trial assessing neoadjuvant atezolizumab (a PD-L1 inhibitor) for resectable NSCLC. Eligible patients with clinical stage IB-IIIB resectable NSCLC received 2 cycles of neoadjuvant atezolizumab (1200 mg, days 1, 22) followed by surgical resection (day 40±10). Pre- and post-treatment PET/CT, pulmonary function tests (PFT), and bio-specimens were obtained. Adverse events (AE) were recorded according to CTCAEv.4.0. Preoperative treatment-related TRAE (preop-TRAE) and postoperative TRAE (postop-TRAE) defined as AE onset on, or after date of surgery, were analyzed. Follow-up data to post-surgery visit were analyzed for 101 patients out of planned 180: mean age: 64.6 years; male: 47/101(46.5%); current smokers: 23/101(22.8%); non-squamous histology: 66/101(65.3%); and clinical stages IB(10.9%), IIA(15.8%), IIB(27.7%), IIIA(38.6%), and IIIB(6.9%). Two cycles of atezolizumab were not completed in 5/101(5.0%) patients due to grade 1 or 2 AEs. Surgery was not performed in 11/101(10.9%) patients: 5 demonstrated disease progression, and 6 for ‘other’ reasons. 6/101(5.9%) patients were deemed unresectable. Surgery was delayed (outside of 10-day window) in 10/90(11.1%) patients by an average of 11(1-39) days. Two of these delays were due to TRAEs (hypothyroidism and pneumonitis), 3 were patient-elected delays, 2 were surgeon-related, and 3 for ‘other’ reasons. Intraoperative vascular complications occurred in 2/90(2.2%) and extensive hilar fibrosis was noted in 20/90(22.2%) patients. Overall, there was insignificant mean change in the PFTs pre- vs. post-atezolizumab therapy. Only 3/101(3.0%) patients had treatment-related dyspnea, dyspnea on exertion, or pneumonitis.Table 1Treatment Related Adverse Events (TRAE)Preoperative TRAE (N = 101)Postoperative TRAE (N = 90)All AEsAny grade55 (54.5%)20 (22.2%)Grade 129 (28.7%)7 (7.8%)Grade 224 (23.8%)9 (10.0%)Grade 32 (2.0%)4 (4.4%)Grade 400Grade 500Specific AEsDyspnea1 (1.0%; grade 2)3 (3.3%; grade 1)Dyspnea on exertion1 (1.0%; grade 1)0Myalgia4 (4.0%; grade 1 or 2)0Hyperthyroidism3 (3.0%; grade 1 or 2)1 (1.1%; grade 1)Hypothyroidism01 (1.1%; grade 2)Pneumonitis1 (1.0%; grade 3)3 (3.3%; grade 2 or 3)Transaminitis (AST or ALT)8 (7.9%; grade 1 or 2)3 (3.3%; grade 1 or 2)Post-atezolizumab Change in Pulmonary Function TestsPFT factorMean change (95% Confidence Interval)FEV1 (N = 72)-0.6% (-2.6% to 1.3%)FVC (N = 72)0.0% (-1.8% to 1.8%)DCLO (N = 64)-1.2% (-4.1% to 1.7%) Open table in a new tab Treatment with neoadjuvant atezolizumab in resectable stage IB-IIIB NSCLC was well tolerated, with minimal delay to surgery, and few treatment associated AEs. This trial continues to accrue and assess MPR, survival, and other long-term endpoints.

To assess outcomes of CT-Guided localization for preoperative lung nodule marking prior to video-assisted thoracoscopic surgery and robotic video-assisted thoracoscopic surgery. 21 CT-guided lung nodule localization procedures were performed on 22 nodules in 21 patients prior to surgical resection. The procedures were performed by a fellowship trained radiologist 1 to 2 hours prior to scheduled surgery under local anesthesia. Approximately 4 to 6 ml of methylene blue/ collagen solution was injected in the perinodular location under CT-guidance with a 19 g trocar needle. Post procedure CT images with increased perinodular consolidation confirmed appropriate marking. Patients were then transferred back to surgery. Accurate perinodular CT-guided needle trocar placement was achieved in all marking procedures. Increased perinodular consolidation was also demonstrated in all patients on the post procedural localized CT scans. One patient with moderate emphysema developed a small to moderate sized pneumothorax and a 8F thoracentesis catheter was placed under CT guidance prior to return to surgery. A second patient developed a tiny pneumothorax which was managed with non-rebreather oxygen mask. There was no noted bleeding or hemoptysis in any of the patients. Methylene blue/ collagen solution was readily visible by the thoracic surgeon in 20 patients and 21 nodules. In one patient, the methylene blue/ collagen was not visualized by the surgeon or present in specimen, although post-marking CT demonstrated perinodular consolidation. Of the 21 identified nodules, pathology specimens confirmed adequacy of nodule resection in all cases. Intraoperative identification of pulmonary nodules/ tumors, especially deep nodules and patients undergoing VATS or robotic surgery, may be challenging. Perinodular localization by CT-guided methylene blue/ collagen solution injection offers a safe technique with high efficacy.

To determine the incidence of toxicity and length of local control for treatment using fast neutron only or mixed fast neutron and photon radiotherapy (RT) for advanced stage non-small cell lung cancer (NSCLC). Between March 1993 and December 2006, 23 patients with AJCC 6th edition Stage IIB-IV NSCLC with cancer confined to the thorax were treated with varying doses of fast neutron and photon RT for their primary lung cancer. Estimated clinical relative biological effectiveness values were 3 for lung and 4 for tumor. Most were treated with mixed fast neutron and photon RT with courses varying from 3-15 Neutron Gy (nGy) plus 10-60 photon Gy (equivalent dose in 2 Gy fractions {EQD2} 54-81 Gy). One patient was treated with neutron RT only to 15 nGy (EQD2 45 Gy). Seventeen of the 23 patients received chemotherapy. Of those receiving chemotherapy, 3 patients had only neoadjuvant chemotherapy, 10 patients had only concurrent chemotherapy, 1 patient had only adjuvant chemotherapy, 2 patients had neoadjuvant and adjuvant chemotherapy, and 1 patient had concurrent and adjuvant chemotherapy. Overall and disease free survival were estimated by the Kaplan-Meier method. Median age at time of treatment was 59 years (Range: 41-71 years). Median follow-up was 5.1 months (Range: 0-29 months). All but 3 patients are known to have died at time of review. Using CTCAE version 4.0, there were no grade 4 toxicities recorded. Three patients developed radiation pneumonitis, and all were grade 3. Twelve patients developed grade 1 or 2 esophagitis. Nine patients developed grade 1 radiation dermatitis and 1 patient had grade 3 radiation dermatitis. Among the 20 patients who had longer than 1 month follow-up, 16 patients (80%) had no evidence of local progression, and the median local control of the other 4 who did recur was 3.3 months (Range: 1-15 months). Median overall survival was 7.4 months (Range: 0-30), and median disease free survival was 2.8 months (Range: 0-22). One year overall survival was 32.4%, and 1-year disease free survival was 5.3%. The use of fast neutron only or mixed fast neutron and photon RT for advanced stage NSCLC was well tolerated with no events of grade 4 toxicities and sustained local control in a majority of patients. Further studies are warranted using hypoxia markers to determine selection of patients who may benefit from this unique modality of treatment.

Purpose/Objective(s)To determine the incidence of toxicity and length of local control for salvage treatment using fast neutron only or mixed fast neutron and photon radiotherapy (RT) for treatment of refractory non-small cell lung cancer (NSCLC).Materials/MethodsBetween April 1993 and May 2006, 20 patients with NSCLC who failed primary treatment with chemotherapy and/or RT were treated with varying doses of fast neutron and photon RT. Estimated clinical relative biological effectiveness values were 3 for lung and 4 for tumor. Courses of fast neutron only RT ranged from 6 to 15 neutron Gy (nGy) (equivalent doses in 2 Gy fractions {EQD2} 18-45 Gy). Mixed courses varied from 5 to 10 nGy plus 6 to 39.6 photon Gray (EQD2 29-79 Gy). Fourteen patients had prior RT, which ranged from EQD2 36 to 90 Gy. Total RT ranged from EQD2 35 to 120 Gy. All except one had previous chemotherapy. Overall and disease free survival was estimated by the Kaplan-Meier method.ResultsMedian age at time of treatment was 61.5 years (Range: 40-82 years). Median follow-up was 1.6 months (Range: 0-28 months). All patients have died at time of review. Using CTCAE version 4.0, there were no grade 3 or 4 toxicities. One patient developed grade 2 radiation pneumonitis, 8 patients developed acute grade 2 esophagitis, and 3 patients developed grade 1 radiation dermatitis. Among the 12 patients who had longer than 1 month follow-up, 6 patients had no evidence of local progression, and the median local control of the other 5 who did recur was 3.1 months. Nine out of the 14 symptomatic patients had successful palliation within a month after completion of treatment. Median overall survival was 2.8 months (Range: 1-28 months), and median disease free survival was 2.6 months (Range: 1-28 months). One year overall survival was 20%, and 1 year disease free survival was 10%. Patients receiving greater than or equal to EQD2 40Gy to the tumor for salvage had statistically significant higher overall median survival (7.8 months vs. 1.2 months p = 0.004).ConclusionsThe use of neutron only or mixed neutron and photon RT for salvage therapy for NSCLC is very well tolerated with no events of grade 3 or higher toxicities, successful palliation in the majority of symptomatic patients, and local control in half of the patients treated. Purpose/Objective(s)To determine the incidence of toxicity and length of local control for salvage treatment using fast neutron only or mixed fast neutron and photon radiotherapy (RT) for treatment of refractory non-small cell lung cancer (NSCLC). To determine the incidence of toxicity and length of local control for salvage treatment using fast neutron only or mixed fast neutron and photon radiotherapy (RT) for treatment of refractory non-small cell lung cancer (NSCLC). Materials/MethodsBetween April 1993 and May 2006, 20 patients with NSCLC who failed primary treatment with chemotherapy and/or RT were treated with varying doses of fast neutron and photon RT. Estimated clinical relative biological effectiveness values were 3 for lung and 4 for tumor. Courses of fast neutron only RT ranged from 6 to 15 neutron Gy (nGy) (equivalent doses in 2 Gy fractions {EQD2} 18-45 Gy). Mixed courses varied from 5 to 10 nGy plus 6 to 39.6 photon Gray (EQD2 29-79 Gy). Fourteen patients had prior RT, which ranged from EQD2 36 to 90 Gy. Total RT ranged from EQD2 35 to 120 Gy. All except one had previous chemotherapy. Overall and disease free survival was estimated by the Kaplan-Meier method. Between April 1993 and May 2006, 20 patients with NSCLC who failed primary treatment with chemotherapy and/or RT were treated with varying doses of fast neutron and photon RT. Estimated clinical relative biological effectiveness values were 3 for lung and 4 for tumor. Courses of fast neutron only RT ranged from 6 to 15 neutron Gy (nGy) (equivalent doses in 2 Gy fractions {EQD2} 18-45 Gy). Mixed courses varied from 5 to 10 nGy plus 6 to 39.6 photon Gray (EQD2 29-79 Gy). Fourteen patients had prior RT, which ranged from EQD2 36 to 90 Gy. Total RT ranged from EQD2 35 to 120 Gy. All except one had previous chemotherapy. Overall and disease free survival was estimated by the Kaplan-Meier method. ResultsMedian age at time of treatment was 61.5 years (Range: 40-82 years). Median follow-up was 1.6 months (Range: 0-28 months). All patients have died at time of review. Using CTCAE version 4.0, there were no grade 3 or 4 toxicities. One patient developed grade 2 radiation pneumonitis, 8 patients developed acute grade 2 esophagitis, and 3 patients developed grade 1 radiation dermatitis. Among the 12 patients who had longer than 1 month follow-up, 6 patients had no evidence of local progression, and the median local control of the other 5 who did recur was 3.1 months. Nine out of the 14 symptomatic patients had successful palliation within a month after completion of treatment. Median overall survival was 2.8 months (Range: 1-28 months), and median disease free survival was 2.6 months (Range: 1-28 months). One year overall survival was 20%, and 1 year disease free survival was 10%. Patients receiving greater than or equal to EQD2 40Gy to the tumor for salvage had statistically significant higher overall median survival (7.8 months vs. 1.2 months p = 0.004). Median age at time of treatment was 61.5 years (Range: 40-82 years). Median follow-up was 1.6 months (Range: 0-28 months). All patients have died at time of review. Using CTCAE version 4.0, there were no grade 3 or 4 toxicities. One patient developed grade 2 radiation pneumonitis, 8 patients developed acute grade 2 esophagitis, and 3 patients developed grade 1 radiation dermatitis. Among the 12 patients who had longer than 1 month follow-up, 6 patients had no evidence of local progression, and the median local control of the other 5 who did recur was 3.1 months. Nine out of the 14 symptomatic patients had successful palliation within a month after completion of treatment. Median overall survival was 2.8 months (Range: 1-28 months), and median disease free survival was 2.6 months (Range: 1-28 months). One year overall survival was 20%, and 1 year disease free survival was 10%. Patients receiving greater than or equal to EQD2 40Gy to the tumor for salvage had statistically significant higher overall median survival (7.8 months vs. 1.2 months p = 0.004). ConclusionsThe use of neutron only or mixed neutron and photon RT for salvage therapy for NSCLC is very well tolerated with no events of grade 3 or higher toxicities, successful palliation in the majority of symptomatic patients, and local control in half of the patients treated. The use of neutron only or mixed neutron and photon RT for salvage therapy for NSCLC is very well tolerated with no events of grade 3 or higher toxicities, successful palliation in the majority of symptomatic patients, and local control in half of the patients treated.