Immune-mediated Pneumonitis Research Articles

First-line treatment with KN046, chemotherapy and palliative radiotherapy for advanced esophageal squamous cell carcinoma: an open-label, dose escalation, and dose expansion phase Ib trial

There is growing evidence to suggest that radiotherapy might enhance the efficacy of immunotherapy. This study aimed to assess the possibility of KN046, a bispecific antibody targeting PD-L1 and CTLA-4, combined with chemotherapy and palliative radiotherapy for advanced esophageal squamous cell carcinoma (ESCC). In this open-label, phase Ib trial, patients with advanced ESCC were administered chemotherapy with palliative radiotherapy, and KN046 in the predefined escalation dosages of 1, 3, or 5 mg/kg (every 3 weeks during chemotherapy cycles and every 2 weeks during KN046 maintenance). The chemotherapy regimen constituted cisplatin (75 mg/m2 i.v., d1) and paclitaxel (135–175 mg/m2 ivgtt., d1). Radiotherapy specifics, including site, timing, dose, and fragmentation pattern, were at the investigator’s discretion. The primary outcome was dose-limiting toxicity (DLT). From May 2019 to April 2021, 25 patients were enrolled across the dosage groups: 3 in 1 mg/kg, 12 in 3 mg/kg, and 10 in 5 mg/kg. No DLT was observed during the dose escalation. The objective response rate was 41.7% (95%CI 22.1–63.4), while the disease control rate was 87.5% (95%CI 67.6–97.3). At a median follow-up of 11.8 months, the median progression-free survival was 7.8 months (95%CI 5.2–9.7) and median overall survival was 15.9 months (95%CI 8.4-NE). Serious adverse events were reported in 48.0% of patients, predominantly leukopenia (16%), immune-mediated enterocolitis (12%), immune-mediated pneumonitis (8%), and neutropenia (8%). Combining KN046 with chemotherapy and palliative radiotherapy might be feasible, showing a favorable safety profile and notable efficacy in advanced ESCC patients.

Neoadjuvant nivolumab + palbociclib + anastrozole for oestrogen receptor-positive/human epidermal growth factor receptor 2-negative primary breast cancer: Results from CheckMate 7A8

BackgroundPreclinical data suggest synergistic activity with the combination of programmed death-1 and cyclin-dependent kinase 4/6 blockade in oestrogen receptor-positive/human epidermal growth factor 2-negative (ER+/HER2–) breast cancer. The noncomparative phase 1b/2 CheckMate 7A8 study (NCT04075604) evaluated neoadjuvant treatment with nivolumab, palbociclib, and anastrozole in patients with ER+/HER2− breast cancer. Here, we report outcomes from the safety run-in phase. MethodsPatients with histologically confirmed, untreated ER+/HER2− breast cancer, primary tumour ≥2 cm, ECOG performance status ≤1, and eligible for post-treatment surgery received nivolumab 480 mg intravenously every 4 weeks, palbociclib 125 mg or 100 mg orally once daily for 3 weeks per cycle, and anastrozole 1 mg orally once daily for five 4-week cycles, or until disease progression. The primary endpoint was the proportion of patients with dose-limiting toxicities (DLTs) within 4 weeks of treatment initiation. ResultsAt safety data review, 21 patients were treated (palbociclib 125-mg group: n = 9; palbociclib 100-mg group: n = 12). DLTs were reported in 2 (22.2%) and 0 patients in the palbociclib 125-mg and 100-mg groups, respectively. Across both groups, 9 patients discontinued treatment due to toxicity (grade 3/4 hepatic adverse events [n = 6], grade 3 febrile neutropaenia [n = 1], grade 1 pneumonitis [n = 1], and grade 3 rash and grade 2 immune-mediated pneumonitis [n = 1]). Consequently, the study was closed early. ConclusionsNeoadjuvant treatment with nivolumab, palbociclib, and anastrozole showed a high incidence of grade 3/4 hepatotoxicity and treatment discontinuation, indicating that this combination should not be further pursued for treatment of primary ER+/HER2− breast cancer.

Updates on the Management of Immunotherapy-Related Toxicities

With the increased use of immune checkpoint inhibition (ICI) comes an increase in the number of patients being treated for immune-related adverse events (irAEs). At the NCCN 2023 Annual Conference, presenters discussed 3 different types of irAEs, namely immune-mediated pneumonitis, major adverse cardiac events including myocarditis and myositis/myasthenia gravis overlap syndrome, and oral toxicities including mucositis and sicca syndrome. They emphasized the importance of considering comorbidities and infectious causes when treating immune pneumonitis. In the context of cardiac events during ICI therapy, the presentation highlighted the need for early detection and vigilance in recognizing insidious, nonspecific symptoms, particularly in cases involving myocarditis with myositis/myasthenia gravis overlap syndrome. Finally, the increasing recognition of oral toxicities was discussed, in addition to the importance of timely intervention to prevent long-term morbidity.

Concurrent sintilimab with sequential chemoradiotherapy for unresectable, stage III non-small cell lung cancer: a retrospective study.

Concurrent programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors with sequential chemoradiotherapy (SCRT) have been reported in only a limited number of studies involving patients with unresectable stage III non-small-cell lung cancer (NSCLC). A retrospective study was conducted to systematically analyze the efficacy and safety of the emerging therapy among Chinese patients. We included patients with unresectable, stage III NSCLC who received concurrent sintilimab with chemotherapy or chemotherapy alone for 3-6 cycles, followed by radical radiotherapy at the First Hospital of Jilin University from Dec 15, 2019, to Jul 15, 2022. The primary end point was the objective response rate (ORR). The secondary end points included progression-free survival (PFS), overall survival (OS), 12-month and 18-month PFS rates, the duration of response (DoR), and safety. The retrospective study involved 77 patients, of which 49 receiving concurrent sintilimab with SCRT were assigned to cohort A, and 28 receiving SCRT alone were assigned to cohort B. The ORR was significantly higher in cohort A (79.6%, 95% CI 65.7-89.8) than in cohort B (35.7%, 95% CI 18.6-55.9) (p<0.001). Median PFS was significantly longer in cohort A than in cohort B (NR [95% CI 21.4-NR] vs. 16.0 months [13.0-22.5]; HR 0.375, 95% CI 0.192-0.735; p=0.003). The PFS rates at 12 and 18 months were 84.8% (95% CI 75.0-95.9) and 71.3% (95% CI 58.7-86.7) in cohort A and 75.0% (95% CI 60.6-92.9) and 38.3% (95% CI 23.7-61.7) in cohort B, respectively. Grade 3 or 4 adverse events (AEs) were reported in 19 patients (38.8%) and seven patients (25.0%) in two cohorts, respectively. Grade 3 or 4 pneumonitis or immune-mediated pneumonitis, radiation pneumonitis, and pneumonia occurred in five (10.2%), four (8.2%), and two (4.1%) cohort A patients, and zero, two (7.1%), and two (7.1%) cohort B patients, respectively. Only cohort A reported AE leading to death in one (2.0%) patient (immune-mediated pneumonitis). Concurrent sintilimab with SCRT resulted in a significantly better ORR and longer PFS than SCRT alone, with manageable safety profiles in Chinese patients with unresectable stage III NSCLC.

A clinical case of immune-mediated pneumonitis after nivolumab in a patient with Burkitt lymphoma

Immunotherapy is a promising method in the treatment of cancer. PD-1 (programmed cell death protein 1) receptor and its ligand, which contribute to the reactivation of T-cells exerting their cytotoxic function against the tumor, are one of the targets of antitumor drugs. The effectiveness of immune checkpoint inhibitors has been demonstrated in the treatment of melanoma and non-small cell lung cancer. The spectrum of side effects of antitumor immune drugs differs from the classical ones observed in the cytostatics treatment. Immune-mediated adverse events can affect multiple organs, including skin, gastrointestinal tract, endocrine and nervous systems, and lungs. Pneumonitis is a potentially life-threatening complication and often requires immediate administration of corticosteroids. This article presents the case of a patient with relapsed Burkitt lymphoma treated with nivolumab and R-ICE (rituximab, ifosfamide etoposide, carboplatin) scheme. The therapy was effective, but complicated by immune-mediated pneumonitis. Corticosteroids administration resolved this complication and anti-cancer treatment was completed. The following nivolumab administrations were free of side effects.

Immune-mediated pneumonitis: A clinical conundrum in a patient with stage IV lung adenocarcinoma with a dramatic and durable response to checkpoint inhibitor case report

Immune checkpoint blockade with pembrolizumab has demonstrated both progression-free survival and overall survival benefit for patients with NSCLC regardless of PD-L1 expression. However, immune-related adverse events, and in particular checkpoint inhibitor pneumonitis (CIP), are common and can complicate the treatment course, duration of response, as well as overall survival. Here we present a patient with stage IV lung adenocarcinoma who experienced a dramatic response following treatment with pembrolizumab, followed by the development of biopsy-proven organizing pneumonia and immune-mediated pneumonitis requiring early treatment discontinuation. The patient has now achieved a near-complete response over 13 months after treatment discontinuation, highlighting the importance of early recognition and management of immune-related adverse events as well as the possibility of durable response despite treatment discontinuation.

Radiation and immune checkpoint inhibitor-mediated pneumonitis risk stratification in patients with locally advanced non-small cell lung cancer: role of functional lung radiomics?

BackgroundPatients undergoing chemoradiation and immune checkpoint inhibitor (ICI) therapy for locally advanced non-small cell lung cancer (NSCLC) experience pulmonary toxicity at higher rates than historical reports. Identifying biomarkers beyond conventional clinical factors and radiation dosimetry is especially relevant in the modern cancer immunotherapy era. We investigated the role of novel functional lung radiomics, relative to functional lung dosimetry and clinical characteristics, for pneumonitis risk stratification in locally advanced NSCLC.MethodsPatients with locally advanced NSCLC were prospectively enrolled on the FLARE-RT trial (NCT02773238). All received concurrent chemoradiation using functional lung avoidance planning, while approximately half received consolidation durvalumab ICI. Within tumour-subtracted lung regions, 110 radiomics features (size, shape, intensity, texture) were extracted on pre-treatment [99mTc]MAA SPECT/CT perfusion images using fixed-bin-width discretization. The performance of functional lung radiomics for pneumonitis (CTCAE v4 grade 2 or higher) risk stratification was benchmarked against previously reported lung dosimetric parameters and clinical risk factors. Multivariate least absolute shrinkage and selection operator Cox models of time-varying pneumonitis risk were constructed, and prediction performance was evaluated using optimism-adjusted concordance index (c-index) with 95% confidence interval reporting throughout.ResultsThirty-nine patients were included in the study and pneumonitis occurred in 16/39 (41%) patients. Among clinical characteristics and anatomic/functional lung dosimetry variables, only the presence of baseline chronic obstructive pulmonary disease (COPD) was significantly associated with the development of pneumonitis (HR 4.59 [1.69–12.49]) and served as the primary prediction benchmark model (c-index 0.69 [0.59–0.80]). Discrimination of time-varying pneumonitis risk was numerically higher when combining COPD with perfused lung radiomics size (c-index 0.77 [0.65–0.88]) or shape feature classes (c-index 0.79 [0.66–0.91]) but did not reach statistical significance compared to benchmark models (p > 0.26). COPD was associated with perfused lung radiomics size features, including patients with larger lung volumes (AUC 0.75 [0.59–0.91]). Perfused lung radiomic texture features were correlated with lung volume (adj R2 = 0.84–1.00), representing surrogates rather than independent predictors of pneumonitis risk.ConclusionsIn patients undergoing chemoradiation with functional lung avoidance therapy and optional consolidative immune checkpoint inhibitor therapy for locally advanced NSCLC, the strongest predictor of pneumonitis was the presence of baseline chronic obstructive pulmonary disease. Results from this novel functional lung radiomics exploratory study can inform future validation studies to refine pneumonitis risk models following combinations of radiation and immunotherapy. Our results support functional lung radiomics as surrogates of COPD for non-invasive monitoring during and after treatment. Further study of clinical, dosimetric, and radiomic feature combinations for radiation and immune-mediated pneumonitis risk stratification in a larger patient population is warranted.

Incidence of safety events after immune checkpoint inhibitor initiation for advanced-stage non-small-cell lung cancer: a real-world study.

Aim: To describe the incidence of safety events after immune checkpoint inhibitor (ICI) initiation for advanced-stage non-small-cell lung cancer. Methods: Retrospective cohort study using the HealthCore Integrated Research Database in the USA to examine the incidence of prespecified safety events of interest after ICI initiation (n=5278). Results: The most common safety events after ICI initiation included malaise/fatigue (incidence rate [IR]:70.7 per 100 person-years; 95% CI:66.5-75.1) and nausea/vomiting (IR:32.4; 30.0-34.8). Other potential immune-mediated events, including colitis (IR:7.11; 6.26-8.04) and pneumonitis (IR:5.47; 4.76-6.25), were less frequent but higher than after any systemic anti-cancer therapy. No safety event rate substantially increased 6months after ICI initiation. Conclusion: This large real-world study reports the incidence of safety events with ICI regimens for advanced-stage non-small-cell lung cancer.

17P Safety and tolerability of sintilimab (sint) combination therapy in patients with advanced or recurrent non-small cell lung cancer (NSCLC): Pooled safety analysis of ORIENT 11 and ORIENT 12 studies

Sint has shown efficacy in randomized, double-blind, phase 3 studies in Chinese patients with NSCLC in ORIENT 11 and ORIENT 12. To further address the safety profile of sint, we present pooled safety and tolerability data from both studies. ORIENT 11 enrolled (2:1) patients with advanced/metastatic nonsquamous NSCLC to receive either sint 200 mg or placebo (pbo) + pemetrexed + platinum once every 3 weeks. ORIENT 12 enrolled (1:1) patients with advanced/metastatic squamous NSCLC to receive either sint 200 mg or pbo + gemcitabine + platinum every 3 weeks. The designs and eligibility of both studies were similar. Pooled analyses were to support the safety assessments by summarizing treatment-related adverse events (TRAE), immune-related TRAE (ir-TRAE) and the association of ir-TRAE with efficacy. Of 754 patients pooled from two studies (ORIENT 11, n=397; ORIENT 12, n=357), 445 were pooled to the sint arm, and 309 to the pbo arm. There were no meaningful differences in baseline characteristics between subjects with or without ir-TRAE in both arms. The TRAE rates were comparable (sint vs pbo: 85.8% vs 81.6%) between the two arms. Although sint arm had higher ir-TRAE occurrence than pbo arm (sint vs pbo: 42.5% vs 30.7%), ≥ Grade 3 ir-TRAE were comparable in both arms (sint vs pbo: 6.1% vs 4.9%). Notably, higher ir-TRAEs were found in sint arm in rash, hypothyroidism, and immune-mediated pneumonitis. TRAE leading to drug discontinuation (sint vs pbo: 6.5% vs 4.2%) and death (sint vs pbo: 0.9% vs 2.3%) are comparable between the two arms. The exploratory analysis indicated that patients experienced ir-TRAE showed longer PFS and OS than those without ir-TRAE in sint arm (Table).Table: 17PEfficacy subgroup analysis by ir-TRAE status in sint armEndpointssint Patients withNEvents, n (%)Median (95%CI), monthHazard ratio (95% CI)Between-group p-value (two-sided)PFSir-TRAE18991 (48.1%)9.0 (6.8, 10.9)0.65 (0.51, 0.82)<0.01no ir-TRAE256148 (57.8%)6.9 (6.0, 7.2)OSir-TRAE18940 (21.2%)NR (NR, NR)0.64 (0.46, 0.90)0.01no ir-TRAE25676 (29.7%)14.9 (13.8, NR)NR= Not Reached Note: Median and 95% CI are estimated based on unstratified Kaplan-Meier method. Hazard ratio and p-value are estimated using a stratified time-dependent Cox proportional hazard regression model. Open table in a new tab NR= Not Reached Note: Median and 95% CI are estimated based on unstratified Kaplan-Meier method. Hazard ratio and p-value are estimated using a stratified time-dependent Cox proportional hazard regression model. Sint in combination with chemotherapy demonstrated a tolerable and manageable safety profile in Chinese patients, generally consistent with the pbo population in ORIENT 11 and ORIENT 12 study.

Characterizing immune-mediated adverse events with durvalumab in patients with unresectable stage III NSCLC: A post-hoc analysis of the PACIFIC trial

IntroductionImmune-mediated adverse events (imAEs), including all-cause immune-mediated pneumonitis, were reported in approximately 25% of patients in the placebo-controlled, phase III PACIFIC trial of durvalumab monotherapy (for up to 12 months) in patients with unresectable, stage III NSCLC and no disease progression after concurrent chemoradiotherapy; only 3.4% of patients experienced grade 3/4 imAEs. With broad application of the PACIFIC regimen (consolidation durvalumab after chemoradiotherapy), now standard-of-care in this setting, there is a need to better characterize the occurrence of imAEs with this regimen. MethodsWe performed descriptive, post-hoc, exploratory analyses to characterize the occurrence of imAEs (pneumonitis and non-pneumonitis) in PACIFIC in terms of: incidence, severity, and timing; clinical management and outcomes; and associations between the occurrence of imAEs and (1) all-cause AEs and (2) baseline patient, disease, and treatment characteristics. ResultsAny-grade immune-mediated pneumonitis (9.4%) and non-pneumonitis imAEs (10.7%) occurred infrequently and were more common with durvalumab versus placebo. Grade 3/4 immune-mediated pneumonitis (1.9%) and non-pneumonitis imAEs (1.7%) were uncommon with durvalumab, as were fatal imAEs (0.8%; all pneumonitis). The most common non-pneumonitis imAEs with durvalumab were thyroid disorders, dermatitis/rash, and diarrhea/colitis. Dermatitis/rash had the shortest time to onset (from durvalumab initiation), followed by pneumonitis; dermatitis/rash had the longest time to resolution, followed by thyroid disorders. Most patients with immune-mediated pneumonitis (78.4%) and non-pneumonitis imAEs (56.3%) had these events occur ≤ 3 months after initiating durvalumab. ImAEs were well managed with administration of systemic corticosteroids, administration of endocrine replacement therapy, and interruption/discontinuation of durvalumab. Time elapsed from completion of prior radiotherapy to trial randomization (<14 vs. ≥ 14 days) did not impact either incidence or severity of imAEs. Durvalumab had a manageable safety profile broadly irrespective of whether patients experienced imAEs. ConclusionThe risk of imAEs should not deter use of the PACIFIC regimen in eligible patients, as these events are generally well managed through appropriate clinical intervention.

A phase Ib, multicenter, open-label study to assess the safety, tolerability, and preliminary efficacy of sintilimab plus IBI310 (anti-CTLA4 mAb) in patients with advanced hepatocellular carcinoma.

421 Background: Immune checkpoint inhibitors (ICI) targeting PD-1/L1 or in combination with CTLA-4 have shown therapeutic benefit in patients with advanced hepatocellular carcinoma (aHCC). This study aimed to evaluate the safety, tolerability, and preliminary efficacy of IBI310, an anti-CTLA-4 monoclonal antibody (mAb), combined with sintilimab, in patients with aHCC who failed or intolerant to previous systemic therapy. Methods: Three cohorts were pre-designed to explore recommended dose of IBI310 in de-escalation order: sintilimab 200 mg plus IBI310 3, 2 or 1 mg/kg every 3 week (q3w). Patients will receive the combined treatment up to 4 cycles, followed by sintilimab 200 mg q3w up to 24 months. Primary endpoint was safety. Key secondary endpoints included objective response rate (ORR), disease control rate (DCR), progress free survival (PFS) and overall survival (OS) by RECISTv1.1 per investigators. Results: 9 subjects were initially treated with sintilimab 200 mg plus IBI310 3 mg/kg q3w without predefined adverse event (AE) observed. 3 mg/kg was determined as recommended dose of IBI310 and no subject was assigned to other cohorts. As of the data cut-off of August 30, 29 subjects were enrolled (median age 51.4 years, 86.2% male, 96.6% BCLC C, 24.1% ICI treated). The average treatment cycles of IBI310 and sintilimab were 2.8 and 5.7. The most frequent treatment related adverse events (TRAEs) of any grade were alanine transaminase increases (34.5%), aspartate transaminase increases (34.5%), thrombopenia (24.1%), and lipase increases (24.1%). Grade ≥3 TRAEs occurred in 34.5% of subjects (including one grade 5 immune-mediated pneumonitis). Dose interruption and discontinuation rates due to AE were 55.2% and 6.9%. With a median follow-up of 9.89 months, investigator confirmed ORR and DCR were 17.2% (all partial response, including one anti-PD1 mAb failed) and 72.4%. The median PFS was 3.9 months (95% CI: 2.6, NR) and median OS not reached (95% CI: 11.4, NR). The 6-month PFS and OS rates were 45.8% (95%CI 25.2%, 64.2%) and 93.1% (95%CI 75.1%, 98.2%) respectively. 6 patients remain on treatment at cutoff date. Conclusions: The combination of sintilimab and IBI310 shows promising efficacy and managable safety profile in aHCC patients. Our results are comparable to that have been published in the same setting. This regimen is currently being evaluated in phase II study. Clinical trial information: NCT04401813.

P28.04 Pneumonitis With Durvalumab Following Concurrent Chemoradiotherapy

Durvalumab consolidation is currently the standard of care for treatment of unresectable stage III non-small cell lung cancer (NSCLC) after concurrent definitive chemoradiation. In our clinical practice and based on more recent reports, clinically significant immune-mediated pneumonitis seems to occur at a higher rate than that seen in trials reaching up to 19%. It is unclear whether chemotherapy regimen influences this risk, though some reports cite taxane-based therapy is associated with increased incidence of radiation pneumonitis.

Development of Skin Rash Predicts Outcome of Anti-PD-1- and Anti-CTLA4-Based Immune Checkpoint Inhibitor Therapy in Non-Small Cell Lung Cancer or Squamous Cell Carcinoma of the Head and Neck: A Single-Center Analysis

Objective: We report the spectrum of immune-related adverse effects (irAEs) and outcome observed in a single-center cohort of 100 patients treated with immune checkpoint inhibitors in a routine clinical setting. Methods: Tumor entities included non-small cell lung cancer (n = 28), head and neck squamous cell carcinoma (n = 28), urothelial carcinoma (n = 7), and others (n = 37). Results: irAEs were documented in 49% of cases analyzed, and the most frequent manifestation consisted of immune-mediated skin rash (28%), colitis (9%), pneumonitis (8%), hypothyroidism (7%), or hepatitis (6%). Skin rash correlated with improved progression-free survival. Conclusion: Development of immune-related skin rash was found to correlate with favorable outcome, suggesting its practical feasibility as a potential predictive surrogate marker.

An Integrated Safety Analysis of the Next Generation PI3Kδ Inhibitor Umbralisib (TGR-1202) in Patients with Relapsed/Refractory Lymphoid Malignancies

An Integrated Safety Analysis of the Next Generation PI3Kδ Inhibitor Umbralisib (TGR-1202) in Patients with Relapsed/Refractory Lymphoid Malignancies

Chemoradiation-induced pneumonitis in patients with unresectable stage III non-small cell lung cancer: A meta-analysis.

e20532 Background: Recent clinical trials have shown positive results for therapies combining concurrent chemoradiation therapy (cCRT) and checkpoint immunotherapy in unresectable non-small cell lung cancer (NSCLC). cCRT is associated with an increased risk of pneumonitis, a severe and life-threatening inflammation of the lungs. To further inform clinical decision-making and support the evaluation of new therapies combining immunotherapies with cCRT, it is important to understand the baseline risk of pneumonitis associated with cCRT alone. The objective of this study was to quantify the incidence of cCRT-induced grade 3−5 pneumonitis (immune-mediated and radiation pneumonitis) in unresectable stage III NSCLC patients. Methods: A systematic literature review and meta-analysis were performed in accordance with PRISMA guidelines. MEDLINE, Embase, and the Cochrane Central Register were searched from 2014 to April 24, 2020. Chemotherapies of interest were cisplatin, pemetrexed, etoposide, carboplatin, and paclitaxel. Randomized controlled trials (RCTs), observational studies, and non-randomized trials were included. Bayesian meta-analysis using a binomial model random effects model was conducted with SAS 9.4. Results: Among 1,889 records identified from the search, 17 studies (6 RCTs, 8 observational studies, 3 single-arm trials) met inclusion criteria. Eleven studies were included in the meta-analysis (5 RCTs, 6 observational studies; 1,788 patients). All studies specified radiation-related pneumonitis (RP), although this is clinically indistinguishable from immune-mediated pneumonitis. Patient populations were comparable across studies; the most common chemotherapies were paclitaxel + carboplatin (n = 6) and pemetrexed + cisplatin (n = 5), and radiation doses ranged from 60–74 Gy. There was variation across studies in intervention, outcome reporting, and follow-up (median range: 12–73 months), but this variation was considered acceptable based on sensitivity analyses. The estimated pooled incidence of grade 3−5 RP in cCRT-treated unresectable stage III NSCLC patients was 3.62% [95% confidence interval (CI): 1.65−6.21] in RCTs and 5.98% [95% CI: 2.26−12.91] in observational studies. The pooled incidence of fatal (grade 5) RP was 0.37% [95% CI: 0−2.78] in RCTs and 1.73% [95% CI: 0.53−4.33] in observational studies. Conclusions: This study estimates that 3.62–5.98% of patients with unresectable stage III NSCLC develop grade 3−5 RP when treated with cCRT, with incidence varying by study design. Estimates of RP incidence were higher in the real-world setting compared to RCTs. These results can be used to contextualize the baseline risk of cCRT-induced pneumonitis in unresectable stage III NSCLC to better understand the adverse event of pneumonitis associated with novel immunotherapy treatments indicated for concomitant use with this modality.

SHR-1701, a bifunctional fusion protein targeting PD-L1 and TGF-β, for advanced NSCLC with EGFR mutations: Data from a multicenter phase 1 study.

9055 Background: Despite the development of targeted therapies for advanced NSCLC harboring EGFR mutations ( EGFR+), acquired resistance remains inevitable. Immune checkpoint inhibitor as monotherapy has limited efficacy. Blockade of the TGF-β pathway which plays a key role in immune suppression may enhance the tumor response to anti-PD-1/PD-L1 antibodies. Here, we assessed SHR-1701, a novel bifunctional fusion protein composed of a mAb against PD-L1 fused with the extracellular domain of TGF-β receptor II, in advanced NSCLC pts including one separate EGFR+ cohort. Methods: This phase 1 study includes a 3+3 dose-escalation and dose-expansion period of pretreated advanced NSCLC and multiple clinical expansion cohorts of different tumor types, genetic aberrations, or prior therapies. During the dose-escalation and dose-expansion period, pathologically confirmed pts received SHR-1701 at 3, 10, or 20 mg/kg Q3W or 20 mg/kg Q2W by intravenous infusion. The primary objectives were to determine the safety profile, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of SHR-1701. In the EGFR+ NSCLC clinical expansion cohort, histologically or cytologically confirmed advanced pts after at least 1L standard EGFR TKI received SHR-1701 at RP2D, and the primary endpoint was objective response rate (ORR). Treatment beyond progression was allowed. Results: During the dose-escalation and dose-expansion period, 30 pts were recruited: all stage IV; 83.3% had ≥2 metastasis sites; 76.7% had received ≥2L prior systemic therapy. One dose-limiting toxicity (immune-mediated pneumonitis) in the 20 mg/kg Q2W group was observed, and the MTD was not reached. Population pharmacokinetics and exposure‐response analysis of SHR-1701 based on this study and another phase 1 study for advanced solid tumors (NCT03710265) demonstrated 30 mg/kg Q3W as the RP2D. In the EGFR+ NSCLC cohort, 27 pts were enrolled: all stage IV; 77.8% had ≥2 metastasis sites; 70.4% had received ≥2L prior systemic therapy; 29.6% had 19-Del, 14.8% 19-Del and T790M, 7.4% 20-ins, 29.6% L858R, 18.5% L858R and T790M. With a median SHR-1701 exposure of 8.7 weeks (range, 3.0-24.0), 4 of the 24 pts who had at least one post-baseline radiographic assessment achieved objective responses, including 3 ongoing confirmed and 1 unconfirmed partial response. ORR was 16.7% (95% CI, 4.7%-37.4%), and disease control rate was 50.0% (95% CI, 29.1%-70.9%). Grade 3 treatment-related adverse events (TRAEs) occurred in 2 (7.4%) pts, including anemia, hypokalemia, and asthenia (1 [3.7%] for each). There were no grade 4 or 5 TRAEs. No pts discontinued treatment due to TRAEs. Conclusions: SHR-1701 monotherapy shows a manageable safety profile and encouraging antitumor activity in advanced EGFR+ NSCLC pts after failure of at least 1L standard EGFR TKI. Further investigation of SHR-1701 combination therapy for EGFR+ NSCLC is warranted. Clinical trial information: NCT03774979.

A phase 2, open-label, multicenter study to evaluate the efficacy, safety, and tolerability of KN046 in combination with chemotherapy in subjects with advanced non-small cell lung cancer.

9060 Background: Dual blockade of PD-1 and CTLA-4 has shown improved overall survival (OS) in combination with a short course of chemotherapy. KN046 is a novel bispecific antibody that blocks both PD-L1 interaction with PD-1/CD80 and CTLA-4 interaction with CD80/CD86. We hypothesized that KN046 could be combined with a full course of chemotherapy and build more durable clinical benefit. Methods: This study enrolled systemic treatment naive, stage IV NSCLC patients (pts). Eligible pts received KN046 plus platinum doublet chemotherapy until progressive disease, unacceptable toxicity, withdrawal of informed consent or death. Efficacy evaluation was performed by investigators per RECIST 1.1. Safety and tolerability were assessed per NCI-CTCAE v5.0. Results: As of the Jan. 19, 2021, 87 pts [Cohort 1 (n = 51), Cohort 2 (n = 36)] have been enrolled with 83 pts having tumor PD-L1 expression data (PD-L1 ≥1%: 55.4%; PD-L1 &lt; 1%: 44.6%). 33.3% pts remained on the study treatment and 66.7% pts discontinued treatment due to disease progression (27.6%), TEAE (13.8%), death (9.2%) and other reasons (16%). The median treatment duration of KN046 was 21 weeks (range: 1.6̃68.7 weeks). Treatment related TEAE (TRAE) occurred in 92% pts. 25.3% pts experienced Grade≥3 TRAE [diarrhoea (5.7%), alanine aminotransferase increased (4.6%), infusion related reaction (3.4%), rash (3.4%), aspartate aminotransferase increased, dermatitis allergic and immune-mediated pneumonitis (2.3%, respectively), anaphylactoid reaction, autoimmune hepatitis, back pain, bilirubin conjugated increased, hypertension, neutrophil count decreased, platelet count decreased, pneumonitis, rash maculo-papular, septic shock and white blood cell count decreased (1.1%, respectively). In 81 efficacy evaluable pts, the overall objective response rate (ORR) was 50.6% (95% CI: 39.3%,61.9%) and disease control rate (DCR) was 87.7% (95% CI: 78.5%-93.9%). The ORR and DCR in pts with non-squamous NSCLC (n = 48) were 45.8% (95% CI: 31.4%, 60.8%) and 89.6% (95% CI: 77.3%, 96.5%). The ORR and DCR in pts with squamous NSCLC (n = 33) were 57.6% (95% CI: 39.2%, 74.5%) and 84.8% (95% CI: 68.1%, 94.9). Progression free survival (PFS) and OS events have occurred in 53% and 18% patients. Median PFS was 5.9 (95%CI: 5.3, 8.7) months. Median OS was not reached. OS rate at 12 and 15 months were both 74.9%. Similar OS curves have been observed in PD-L1 ≥1% and PD-L1 &lt; 1% pts. In PD-L1 ≥1% patients, median PFS was 6.7 months (10.8 months for PD-L1 ≥1% squamous NSCLC pts). Conclusions: KN046 combined with platinum doublet chemotherapy is tolerated and has shown promising clinical benefit as IL treatment for stage IV NSCLC particularly in PD-L1≥1% tumors and squamous histology. Pivotal Phase III trial in advanced unresectable or metastatic squamous NSCLC is currently ongoing. Clinical trial information: NCT04054531.

P09.54 Pneumonitis Following Durvalumab: A Real-World Analysis in Patients with Lung Cancer and Other Tumor Types

Durvalumab, a PDL-1 inhibitor is the standard of care as consolidation therapy after chemoradiotherapy for unresectable stage III non-small cell lung cancer (NSCLC) in the United States (US). Immune-mediated pneumonitis occurs with all checkpoint inhibitors, however patients with lung cancer may be particularly susceptible. In the PACIFIC trial supporting approval of durvalumab for this indication, any pneumonitis was reported in 34% of durvalumab-treated patients vs. 24% of placebo-treated patients. Pneumonitis represented 34% of all adverse events (AEs) in the study and led to treatment discontinuation in 6% durvalumab-treated patients (Antonia et al, NEJM 2018). Durvalumab is also approved in the US for recurrent urothelial cancer, but only 1% of patients experienced pneumonitis in the supporting trial. We conducted an analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) database to evaluate post-marketing cases of pneumonitis reported in patients treated with durvalumab for NSCLC vs. other tumor types. The FAERS database, which contains anonymized reports of product-related AEs classified using the Medical Dictionary for Regulatory Activities and categorized as serious or non-serious, was queried for cases of pneumonitis in patients treated with durvalumab for oncology indications from the Food and Drugs Administration (FDA) approval date (May 1, 2017) through June 30, 2020. Cases occurring outside the US and cases for which the indication was not specified were excluded. The indication for use, reported demographics and AE outcomes were collected. The association of pneumonitis with indication and AE seriousness was evaluated by Chi-square test, using a two-sided α=0.05 to determine statistical significance. Median age in each subgroup was compared using the Mann-Whitney U test. Of the 733 durvalumab-associated AE cases retrieved, (532 [73%] for NSCLC, 201 [27%] for other tumor types), a total of 130 reports of any pneumonitis were identified. Pneumonitis accounted for 122 of 532 (23%) of all AEs reported in NSCLC vs. 8 of 201 (4%) in other tumor types (p<0.01). A greater proportion of pneumonitis cases were categorized as serious compared to non-pneumonitis cases (125 of 130 [96%] vs. 421 of 603 [70%], p<0.01). There was no difference between pneumonitis and non-pneumonitis cases in reported deaths (25 of 130 [19%] vs. 101 of 603 [17%]) or hospitalizations (57 of 130 [44%] vs. 242 of 603 [40%]). The median age of patients in pneumonitis cases was older than patients in non-pneumonitis cases (71 vs. 66 years, p<0.01). The proportion of durvalumab-associated AE cases reporting pneumonitis was greater for NSCLC vs. other tumor types and increased with age but was not associated with higher deaths or hospitalizations. Pneumonitis constituted a lesser proportion of total AEs in this real-world cohort compared to the PACIFIC trial. Limitations of this retrospective analysis include the potential for under-reporting of AEs to the FAERS database, the inability to establish causality, and the lack of a true denominator. Despite the limitations, these AE findings from a real-world dataset complement clinical trial safety data and support further investigation of interaction of chemoradiotherapy with checkpoint inhibitors in the pathogenesis of pneumonitis.

Nivolumab Immune-Mediated Pneumonitis.

Nivolumab Immune-Mediated Pneumonitis.

Radiological Imaging of Adverse Events to Immunotherapy

At present, immunotherapy is successfully used for the treatment of multiple malignant diseases, especially in the late stages of metastatic tumors, which until now, were difficult to treat using standards protocols. Positive therapeutic effects of immunotherapy were demonstrated in treatment of many common oncological diseases. However, despite the expressed positive effect, in some patients immunotherapy can demonstrate non-typical forms of the answer. To establish accurate diagnosis it is necessary to know radiological manifestations of immune-related adverse events (irAE), mainly, immune-mediated pneumonitis, colitis, hypophysitis, hepatitis and myositis. Early identification and the corresponding treatment of irAE may improve patient's outcomes.