Pretreated Advanced Non-small Cell Lung Cancer Research Articles

SHR-A1811 (antibody-drug conjugate) in advanced HER2-mutant non-small cell lung cancer: a multicenter, open-label, phase 1/2 study

A dose-escalation and expansion, phase 1/2 study (ClinicalTrials.gov, NCT04818333) was conducted to assess the novel antibody-drug conjugate SHR-A1811 in pretreated HER2-altered advanced non-small cell lung cancer (NSCLC). Here, we report results from the phase 1 portion. Patients who had previously failed or were intolerant to platinum-based chemotherapy were enrolled and received SHR-A1811 intravenously at doses of 3.2 to 8.0 mg/kg every 3 weeks. Dose escalation followed a Bayesian logistic regression model that included overdose control, with subsequent selection of tolerable levels for dose expansion. Overall, 63 patients were enrolled, including 43 receiving a recommended dose for expansion of 4.8 mg/kg. All patients had HER2-mutant disease. Dose-limiting toxicity occurred in one patient in the 8.0 mg/kg dose cohort. Grade ≥ 3 treatment-related adverse events occurred in 29 (46.0%) patients. One patient in the 6.4 mg/kg cohort died due to interstitial lung disease. As of April 11, 2023, the 4.8 mg/kg cohort showed an objective response rate of 41.9% (95% CI 27.0–57.9), and a disease control rate of 95.3% (95% CI 84.2–99.4). The median duration of response was 13.7 months, with 13 of 18 responses ongoing. The median progression-free survival was 8.4 months (95% CI 7.1–15.0). SHR-A1811 demonstrated favourable safety and clinically meaningful efficacy in pretreated advanced HER2-mutant NSCLC.

Abstract CT247: Updated efficacy and safety of anti-TROP2 ADC SKB264 (MK-2870) for previously treated advanced NSCLC in Phase 2 study

Abstract Background: TROP2 (trophoblast cell surface antigen 2) is commonly over-expressed in non-small cell lung cancer (NSCLC) and associated with poor prognosis. SKB264 (MK-2870) is a TROP2 ADC developed with a novel linker to conjugate the payload, a belotecan-derivative topoisomerase I inhibitor. The linker is affected by both extracellular pH-sensitive cleavage and intracellular enzymatic cleavage within tumor cells, which leads to efficiently release payload inside tumor cells as well as within tumor microenvironment to exert its anti-tumor effects. Here, we present the updated data from a Phase 2 expansion cohort for patients (pts) with advanced NSCLC. Methods: Pts with previously treated advanced NSCLC were enrolled to receive SKB264 at 5 mg/kg Q2W until disease progression or unacceptable toxicity (KL264-01, NCT04152499). Tumor assessment was performed every 8 weeks per RECIST v1.1 assessed by investigator. Results: As of Nov 22, 2023, 43 NSCLC pts had been enrolled. Median follow-up was 17.2 months (mo). 21 pts with EGFR wild type had received median prior 3 regimens of therapy including anti-PD-1/L1 inhibitors. 22 pts with EGFR mutant had progressed on or after TKI therapy, 50% of whom also failed at least one line of chemotherapy. Updated efficacy results are shown in the Table. Overall, 30 pts (69.8%) experienced Grade ≥3 treatment-related adverse events (TRAEs). The most common Grade ≥3 TRAEs were neutrophil count decreased (34.9%), anemia (30.2%), WBC count decreased (25.6%), stomatitis (9.3%), and rash (7.0%). No TRAEs leading to treatment discontinuation or deaths occurred. No drug-related ILD/pneumonitis was reported. Conclusions: The updated data continues to demonstrate that SKB264 monotherapy delivers promising clinical efficacy with manageable toxicity in pretreated advanced NSCLC pts. A Phase 3 global study of SKB264 in pts with 3L+ EGFR mutant NSCLC (NCT06074588) and a Phase 3 study of SKB264 in China in pts with 2L EGFR mutant NSCLC (NCT05870319) are ongoing. TABLE 1: NAND Table Clinical outcomes by EGFR mutation status Overall (N=43) EGFR mutant (N=22) EGFR wild type Total (N=21) Non-squamous (N=9) Squamous (N=12) ORR*, % 43.6% 60.0% 26.3% 22.2% 30.0% Median DoR, mo (95%CI) 9.3 (3.7, 10.3) 8.7 (3.7, 10.3) 9.6 (3.5, NE) / / Median PFS, mo (95% CI) 7.2 (5.4, 11.3) 11.5 (5.7, 12.9) 5.3 (3.5, 6.2) 5.8 (1.5, 12.1) 5.1 (1.9, 9.3) Median OS, mo (95% CI) 22.6 (13.1, NE) 22.7 (19.7, NE) 14.1 (10.7, NE) 16.2 (5.8, NE) 12.8 (3.5, NE) 12-mo OS rate, % (95% CI) 69.0% (52.7, 80.7) 81.0% (56.9, 92.4) 57.1% (33.8, 74.9) 66.7% (28.2, 87.8) 50.0% (20.8, 73.6) 18-mo OS rate, % (95% CI) 56.5% (40.1, 70.0) 76.2% (51.9, 89.3) 35.9% (16.0, 56.4) 44.4% (13.6, 71.9) 30.0% (7.7, 56.9) *Including confirmed or unconfirmed response. Based on response evaluable pts (≥1 on-study scans) with 4 pts (2 EGFR mutant pts with non-squamous histology and 2 EGFR wild type pts with squamous histology) excluded. Citation Format: Wenfeng Fang, Ying Cheng, Zhendong Chen, Wei Wang, Yongsheng Li, Yongmei Yin, Xingya Li, Huiting Xu, Guohua Yu, Yanjun Mi, Zev A. Wainberg, Jordi Rodon, Xiang Wang, Xian Wang, Xiaoqing Zhang, Xiaoping Jin, Lian Lu, Junyou Ge, Jin Li, Li Zhang. Updated efficacy and safety of anti-TROP2 ADC SKB264 (MK-2870) for previously treated advanced NSCLC in Phase 2 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT247.

Intracranial efficacy of sotorasib versus docetaxel in pretreated KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC): Practice-informing data from a global, phase 3, randomized, controlled trial (RCT).

LBA9016 Background: Brain metastases are common (~30%) in patients (pts) with KRAS G12C-mutated advanced NSCLC and have a negative impact on survival and quality of life (QOL). In the CodeBreaK 200 global, phase 3 RCT, sotorasib was the first oral KRASG12C inhibitor to show improved progression-free survival (PFS) and overall response rate (ORR), with a better toxicity profile and QOL, compared with intravenous docetaxel in pretreated KRAS G12C-mutated advanced NSCLC. Here we describe the first RCT data evaluating the intracranial (IC) efficacy of sotorasib versus docetaxel from the CodeBreaK 200 study. Methods: Pts with KRAS G12C-mutated advanced NSCLC who progressed after platinum-based chemotherapy and a checkpoint inhibitor were randomized 1:1 to sotorasib (960 mg daily; n=171) or docetaxel (75 mg/m2 every 3 weeks; n=174). Patients with treated, stable (non-progressing) brain metastases were eligible for study. Baseline brain imaging, by contrast enhanced MRI, was performed for all pts at screening. For pts with history of or brain metastasis at baseline, the brain MRI was repeated at every subsequent imaging assessment (every 6 weeks). A post-hoc analysis on IC efficacy (CNS PFS and time to CNS recurrence) was assessed by blinded independent central review (BICR) per modified Response Assessment in Neuro-Oncology Brain Metastases (mRANO-BM). Systemic response was also assessed by RECIST 1.1. Results: CNS metastases by imaging at baseline were present in 40 pts (23%) in the sotorasib arm and 29 pts (17%) in the docetaxel arm (full analysis set, FAS). With a median follow-up of 20.0 months, the median systemic PFS by RECIST 1.1 in the FAS was 6.1 months versus 4.5 months (HR 0.57 [95% CI: 0.30, 1.07], P=0.045) for sotorasib versus docetaxel, respectively. Time to CNS recurrence in the FAS was 9.6 months with sotorasib versus 5.4 months with docetaxel (HR 0.84 [95% CI: 0.32, 2.19], P=0.37). Treatment-related adverse events of any grade occurred in 77.5% of pts treated with sotorasib versus 89.7% of pts treated with docetaxel. Conclusions: In the first randomized evaluation of IC activity of any KRASG12C inhibitor, sotorasib demonstrated a reduced risk of progression and trend towards delayed time to CNS recurrence versus docetaxel in patients with pretreated KRAS G12C-mutated advanced NSCLC who had treated, stable brain metastases. These results suggest IC activity with sotorasib to complement the overall PFS benefit observed with sotorasib versus docetaxel. Clinical trial information: NCT04303780 .

Biomarker subgroup analyses of CodeBreaK 200, a phase 3 trial of sotorasib versus (vs) docetaxel in patients (pts) with pretreated KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC).

9008 Background: Sotorasib is a first-in-class oral, irreversible KRASG12C inhibitor approved for adults with pretreated KRAS G12C-mutated advanced NSCLC. In CodeBreaK 200, the first KRASG12C inhibitor randomized phase 3 trial, sotorasib demonstrated superior progression-free survival (PFS) and overall response rate (ORR) vs docetaxel and a more favorable safety profile. We report prespecified exploratory biomarker analyses comparing sotorasib vs docetaxel efficacy in molecularly-defined KRAS G12C-mutated advanced NSCLC subsets. Methods: In CodeBreaK 200, 345 pts with KRAS G12C-mutated advanced NSCLC who progressed after platinum-based chemotherapy and a checkpoint inhibitor were randomized 1:1 to oral sotorasib 960 mg daily or IV docetaxel 75 mg/m2 Q3W. Primary endpoint was PFS by blinded independent central review (RECIST 1.1; key secondary endpoint: ORR). In prespecified exploratory analyses, baseline tissue and plasma samples were analyzed for key genomic alterations (eg, STK11, KEAP1, EGFR, MET, TP53), by central targeted next-generation sequencing (Skoulidis N Engl J Med 2021), and PD-L1 protein level by local standard of care testing in biomarker-evaluable cases; biomarker status was correlated with PFS and ORR. Inferred tumor mutation burden by plasma circulating tumor DNA (sum of mutant molecular variant reads) was assessed. Association of baseline genomic alterations with long-term benefit (PFS ≥ 6 m) vs early progression (PFS < 3 m; no complete/partial response) was evaluated. Results: Most prevalent KRAS G12C co-alterations in biomarker-evaluable cases with available tumor and/or plasma samples (n=317) were TP53 (181 [57.1%]), STK11 (119 [37.5%]), and KEAP1 (82 [25.9%]) in CodeBreaK 200, consistent with CodeBreaK 100; 55 (17.4%) pts had STK11 and KEAP1 co-alterations. Sotorasib showed superior clinical benefit vs docetaxel independently of PD-L1 expression and across all prespecified subgroups (eg, STK11, KEAP1, TP53) . No clinical response occurred with either treatment in 26 (8.2%) pts with additional KRAS alterations, including amplifications. High baseline plasma tumor burden was associated with greater odds of early progression vs long-term benefit in both arms (odds ratio, 3.54 [95%CI 1.83-6.85] per tertile increase; p<0.0001). Correlation of KRAS G12C co-alterations with response detected a signal toward shorter median PFS (sotorasib, 2.8 m [95%CI 1.6-3.4]; docetaxel, 7.5 m [95%CI 3.0-NE]) with sotorasib vs docetaxel in pts with KRAS G12C and NOTCH1 co -altered tumors. Conclusions: Sotorasib demonstrated consistent clinical benefit vs docetaxel in all prespecified molecularly-defined subgroups (eg, STK11, KEAP1, TP53) in this exploratory analysis of CodeBreaK 200. No predictive biomarkers were confirmed, but novel hypothesis-generating signals were observed. Clinical trial information: NCT04303780 .

Results from a first-in-human phase 1B study of a complement factor H inhibitor (GT103) in patients with non-small cell lung cancer (NSCLC).

9128 Background: GT103 is a first-in-class IgG3 monoclonal antibody that was derived from a single human B cell and inhibits complement factor H (CFH). CFH is implicated in cancer immune evasion and overexpression portends a poor prognosis in multiple malignancies. CFH regulates C3 convertase in the alternative pathway of the complement cascade, limiting downstream opsonization and membrane attack complex formation. Monoclonal antibody inhibition of CFH facilitates complement-dependent tumor cell lysis, modulates the adaptive immune response, and inhibits tumor growth. Methods: GT103 is being evaluated in a multi-institutional, first-in-human, phase Ib study in patients with advanced stage, refractory NSCLC. A standard ‘3+3’ dose escalation schema was used across four dose levels, with treatment given until disease progression or unacceptable toxicity. Dose limiting toxicity (DLT) observation period included cycle 1 and radiographic disease assessment was performed every 6 weeks. We have previously reported that no DLT was seen at the highest two dose levels of 3 mg /kg or 10 mg/kg administered IV every 3 weeks. Two expansion cohorts have now been opened at 10 mg/kg IV every 2 week and 15 mg/kg every 3 weeks dose levels allowing up to 6 patients at each dose level. We herein present updated clinical outcomes and analysis of correlative biomarkers. Results: As of February 3, 2023, twenty-five patients have been treated, with a median follow up of 230 days. Five of the 21 patients in the dose escalation cohort demonstrated stable disease by RECIST criteria. In the 10 mg/kg dose level, one patient has experienced prolonged disease stabilization and has received 12 cycles to date with tumor reduction on CT. The DLT period is ongoing for two patients enrolled in the 10 mg/kg IV every 2 weeks and two patients in the 15 mg/kg every 3 weeks expansion cohorts. Soluble C5b-9 (s C5b-9) is a candidate pharmacodynamic biomarker for GT103 and was measured at baseline and at day 15 from patients in all four dose escalation levels (0.3, 1, 3, 10 mg/kg). An increase in sC5b-9 was found in 13 of 21 patients at day 15. A marked doubling of the baseline sC5b-9 level was demonstrated in a subset of patients by day 15 indicative of biologic activity. Conclusions: GT103 is well tolerated in heavily pretreated advanced NSCLC population. Early clinical activity has been demonstrated to date with stable disease seen in 24% of patients. Updated clinical results and correlative data will be presented. A separate phase 2 study of combination GT103 with pembrolizumab is planned for patients with refractory NSCLC. Trial Registration: The study was approved by Duke University IRB with approval number Pro00104564. Clinical trial information: NCT04314089 .

Multi-Institutional Randomized Phase II Trial of Gefitinib for Previously Treated Patients With Advanced Non-Small-Cell Lung Cancer.

To evaluate the efficacy and tolerability of two doses of gefitinib (Iressa [ZD1839]; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with pretreated advanced non-small-cell lung cancer (NSCLC). This was a randomized, double-blind, parallel-group, multicenter phase II trial. Two hundred ten patients with advanced NSCLC who were previously treated with one or two chemotherapy regimens (at least one containing platinum) were randomized to receive either 250-mg or 500-mg oral doses of gefitinib once daily. Efficacy was similar for the 250- and 500-mg/d groups. Objective tumor response rates were 18.4% (95% confidence interval [CI], 11.5 to 27.3) and 19.0% (95% CI, 12.1 to 27.9); among evaluable patients, symptom improvement rates were 40.3% (95% CI, 28.5 to 53.0) and 37.0% (95% CI, 26.0 to 49.1); median progression-free survival times were 2.7 and 2.8 months; and median overall survival times were 7.6 and 8.0 months, respectively. Symptom improvements were recorded for 69.2% (250 mg/d) and 85.7% (500 mg/d) of patients with a tumor response. Adverse events (AEs) at both dose levels were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent in the higher-dose group. Withdrawal due to drug-related AEs was 1.9% and 9.4% for patients receiving gefitinib 250 and 500 mg/d, respectively. Gefitinib showed clinically meaningful antitumor activity and provided symptom relief as second- and third-line treatment in these patients. At 250 mg/d, gefitinib had a favorable AE profile. Gefitinib 250 mg/d is an important, novel treatment option for patients with pretreated advanced NSCLC.

Short-term dynamics of circulating tumor DNA predicting efficacy of sintilimab plus docetaxel in second-line treatment of advanced NSCLC: biomarker analysis from a single-arm, phase 2 trial

ObjectiveRobust biomarker predicting efficacy of immunotherapy is limited. Circulating tumor DNA (ctDNA) sought to effectively monitor therapeutic response as well as disease progression. This study aims to investigate predictive role...

Cost-Effectiveness of Tislelizumab Versus Docetaxel for Previously Treated Advanced Non-Small-Cell Lung Cancer in China.

Background: Tislelizumab, a new high-affinity programmed cell death protein-1 (PD-1) inhibitor, significantly prolonged the overall survival in pretreated non-small-cell lung cancer (NSCLC). This study aimed to assess the cost-effectiveness of tislelizumab versus docetaxel for this population in China. Methods: A three-state partitioned survival model was developed to simulate advanced NSCLC. Efficacy and safety data were based on a global phase 3 clinical trial (RATIONALE 303). Utilities were mainly extracted from previously published resources. Costs were calculated from the Chinese healthcare system’s perspective, and only direct medical costs were covered. The main outcomes included total costs, life years (LYs), quality-adjusted life years (QALYs), and incremental cost effectiveness ratio (ICER). One-way and probabilistic sensitivity analyses were carried to test the uncertainty of the modeling results. In addition, several scenarios including tislelizumab price before negotiation, different docetaxel price calculation, 50-year time horizon, and alternative utility values were assessed. Results: The model predicted an average gain of 0.62 LYs and 0.51 QALY for tislelizumab vs. docetaxel, at the additional cost of $9,219. The resulting ICER was $15,033.92/LY and $18,122.04/QALY, both below the cost-effective threshold (CET) of three times gross domestic product (GDP) per capita in China. Sensitivity analyses showed that the results are robust over a plausible range for majority of inputs. Utility of progression-free survival (PFS), followed by the price of tislelizumab, had the greatest impact on the ICER. The probability of being cost-effective for tislelizumab was 96.79% at the CET we set. Conclusion: Tislelizumab improves survival, increases QALYs, and can be considered a cost-effective option at current price compared with docetaxel for pretreated advanced NSCLC in China.

Validation of an immunohistochemical assay, CEACAM5 IHC 769, under development for use with the antibody-drug conjugate tusamitamab ravtansine (SAR408701).

e21030 Background: Despite recent advances in non-small cell lung cancer (NSCLC) treatment, a need remains for treatment options at disease progression. Tusamitamab ravtansine (SAR408701) is an antibody-drug conjugate of a humanized CEACAM5-specific monoclonal antibody linked to the maytansinoid DM4, a potent anti-tubulin agent. In a Phase 1/2 study, tusamitamab ravtansine showed promising antitumor activity in pretreated advanced non-squamous NSCLC (NSQ NSCLC) patients with high CEACAM5 expression, defined as ≥ 50% of the tumor cells per specimen with CEACAM5 positive staining at ≥ 2+ intensity (Gazzah A et al. J Clin Oncol 2020;38[15]: 9505). Sanofi and Agilent have partnered to develop an immunohistochemical (IHC) assay, CEACAM5 IHC 769, for detection of CEACAM5 protein in formalin-fixed paraffin-embedded (FFPE) NSQ NSCLC tissue using the EnVision FLEX visualization system on Dako Omnis. This assay is in development for the assessment of patients for whom tusamitamab ravtansine is being considered. Methods: CEACAM5 IHC 769 is a qualitative IHC assay using mouse monoclonal anti-CEACAM5 clone 769. Murine anti-CEACAM5 clone 769 is based on tusamitamab ravtansine, with the same specificity as the drug for CEACAM5. The clone was developed by Sanofi and used to evaluate CEACAM5 expression in a Phase 1/2 trial. The CEACAM5 IHC 769 scoring algorithm defines positive staining as any partial or complete tumor cell plasma membrane staining at ≥ 2+ intensity. Membrane staining may be linear or punctate. Staining may appear as complete or partial staining involving the basal, lateral, or basolateral aspects of the membrane, or as apical staining of the luminal aspect of the cell. CEACAM5 IHC 769 is being validated by Agilent Technologies for NSQ NSCLC at the cutoff of ≥ 50% at ≥ 2+ intensity. Internal studies included sensitivity, specificity, intra-block heterogeneity, observer precision, laboratory repeatability/precision, and robustness. Results: Sensitivity studies demonstrated detection across a dynamic range of CEACAM5 expression. Specificity studies indicated that the antibody is specific for CEACAM5. An intra-block heterogeneity study showed good overall diagnostic agreement for sections from the same tumor (point estimate ≥ 85%). Inter- and intra-observer precision, laboratory repeatability/precision, and robustness validation studies met acceptance criteria; the lower bound of the two-sided 95% confidence interval was ≥ 85% for positive, negative, and overall percent agreement. Conclusions: Internal validation studies demonstrated that CEACAM5 IHC 769 is sensitive, specific, precise, reproducible and robust in evaluating CEACAM5 expression in NSQ NSCLC tissue at the cutoff of ≥ 50% at ≥ 2+ intensity. CEACAM5 IHC 769 is being used for patient selection/stratification in ongoing Phase 2 and 3 clinical trials of tusamitamab ravtansine.

Combination of trastuzumab, pertuzumab and docetaxel in patients with advanced non-small cell lung cancer (NSCLC) harboring HER2 mutation: Final results from the IFCT-1703 R2D2 trial.

9015 Background: Human epidermal growth factor receptor 2 ( HER2) exon 20 insertions and mutations are oncogenic drivers found in 1-2% of NSCLC. However, there are no approved therapies for these patients. Many studies suggest that the use of HER2 inhibitors developed for breast cancer patients might be of interest in this setting. The aim of this trial was to prospectively evaluate the interest of a combination of two antibodies against HER2 (trastuzumab and pertuzumab) with docetaxel. Methods: IFCT-1703 R2D2 trial is a multicenter, non-randomized phase 2 study with a two-stage design, a power of 90% and an alpha risk at 5% (one-sided). HER2 mutational status was assessed locally in certified molecular genetic centers. Main other inclusion criteria were advanced NSCLC, progression after ≥ 1 platinum-based chemotherapy, asymptomatic brain metastases, left ventricular ejection fraction (LVEF) ≥ 50%, and PS 0-2. Patients were treated every 3 weeks with pertuzumab at a loading dose of 840 mg, and 420 mg thereafter; plus trastuzumab at a loading dose of 8 mg/kg and 6 mg/kg thereafter; and docetaxel at 75 mg/m². Treatment was given until toxicity or disease progression. The primary outcome was overall response rate (ORR). Other endpoints included duration of response, progression-free survival and safety. NCT number: NCT03845270. Results: From May 2019 to October 2020, 45 patients were enrolled in 17 centers and received study treatment. Median age was 64.5 years (range 31–84), 72% females, 35% smokers, 100% non-squamous histology and 15% with ECOG PS 2. 31.1% patients had brain metastases. PD-L1 was expressed ≥ 1% and ≥ 50% in 36% and 7% of the patients, respectively. No other oncogene driver was found associated with HER2 exon 20 mutation. With a median follow-up of 12 months, 44 (98%) patients were evaluable for the primary endpoint. Overall response rate was 29% (n = 13), stable disease 56% (n = 26). Median PFS was 6.8 months (95% CI[4.0-8.5]). Median duration of treatment in patients with confirmed response (n = 13) was 10 months (95% CI[2.7-14.9]). At the time of data cut-off, 15 patients (33%) were still under treatment. Grade 3/4 treatment-related adverse events (AEs) were observed in 64% of patients. No patient experienced treatment discontinuation because of toxicity. One sudden death was possibly related to treatment. Most frequent grade ≥ 3 AEs were neutropenia (33%), diarrhea (13%) and anaemia (9%). Grade 1/2 dyspnea was observed in 3 (6.7%) patients. No ILD were reported. Variation LVEF was -1.72% on average (min: -18 %; max: 10 %). Conclusions: The triplet trastuzumab, pertuzumab and docetaxel is feasible and active in HER2 pretreated advanced NSCLC. These results confirm the activity of HER2 antibodies-based strategy which should be considered in these patients. Clinical trial information: NCT03845270.

Clinical implications of germline BCL2L11 deletion polymorphism in pretreated advanced NSCLC patients with osimertinib therapy

IntroductionB-cell lymphoma 2-like 11 (BCL-2-like 11, BCL2L11, also known as BIM) deletion polymorphism (BIM-del) has been associated with resistance to first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), and is a poor prognostic factor for EGFR-mutant non-small-cell lung cancer (NSCLC) patients. Nevertheless, the impact of BIM-del in advanced NSCLC patients treated with the third-generation EGFR-TKI osimertinib remains undetermined. This study aims to evaluate the relationship between BIM-del and therapeutic efficacy of osimertinib in pretreated NSCLC patients. MethodsPatients subjected to EGFR T790 M detection and prior osimertinib treatment between December 2015 and December 2019 in our hospital were enrolled in this study. Peripheral blood samples from these patients were collected to detect BIM-del by polymerase chain reaction. Cox proportional hazards models were used to analyze the clinical outcomes of patients with and without BIM-del. ResultsIn total, 152 Chinese Han NSCLC patients—including 143 T790M-positive and nine T790M-negative patients—were enrolled. BIM-del was detected in only 17.5 % of T790M-positive patients (25/143). The majority of patients were aged <65 years (81.8 %, 117/143), were female (58.7 %, 84/143), were non-smokers (82.5 %, 118/143), had Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–1 (88.8 %, 129/143), and exhibited metastases in the central nervous system (CNS) (54.5 %, 78/143). There were no associations between the BIM-del and clinical characteristics (including age, sex, histology, smoking status, stage, ECOG PS score, and CNS metastases). Patients with BIM-del had a poorer objective response rate than those without (28.0 % versus 52.5 %, p = 0.026). Besides, BIM-del was associated with a significantly shorter progression-free survival (PFS) and a moderately shorter overall survival (OS) (8.3 versus 10.5 months, p = 0.031 and 15.9 versus 25.2 months, p = 0.1, respectively). Multivariate analysis indicated that BIM-del was an independent prognostic factor for PFS but not for OS in EGFR T790 M NSCLC patients. ConclusionsBIM-del is associated with poor clinical responses and outcomes, and might be a negative predictive and prognostic biomarker in EGFR T790 M NSCLC patients with osimertinib treatment.

535TiP - Phase II study of atezolizumab for pretreated advanced / recurrent non-small cell lung cancer with idiopathic interstitial pneumonia (TORG1936 / AMBITIOUS study)

BackgroundInterstitial pneumonia (IP) is one of the most common and poor prognostic comorbidities in patients with non-small cell lung cancer (NSCLC) and is also a known risk factor for pneumonitis. Approximately 10% of patients have concomitant IP diagnosed at the time of cancer diagnosis. IP is associated with smoking, microsatellite instability (MSI) and higher tumour mutation burden (TMB). Atezolizumab monotherapy is an established treatment for recurrent NSCLC. PD-L1 inhibitors are reported to have a lower risk of pneumonitis than PD-1 inhibitors. This study aims to assess the safety and efficacy of atezolizumab monotherapy for pretreated advanced or recurrent NSCLC patients with idiopathic IP. Trial designThe Thoracic Oncology Research Group (TORG) 1936/AMBITIOUS study is a multicentre, single-arm, phase II trial. The key inclusion criteria are (1) histologically or cytologically proven NSCLC, (2) unresectable stage III/IV or recurrent disease, (3) prior chemotherapy, including platinum doublet chemotherapy, (4) chronic, fibrotic and idiopathic IP with a predicted vital capacity ≥ 70%, (5) age ≥ 20 years and (6) ECOG performance status 0, 1. The enrolled patients will receive atezolizumab (1200 mg) every 3 weeks until the discontinuation criteria are satisfied. The primary end point is the 1-year survival rate. We set an expected value of 40% and a threshold value of 15%. Taking statistical points (two-sided α = 0.05; 1 − β = 0.9) and ineligible patients into account, the sample size was set at 38 based on the exact binomial test. The key secondary end points are the incidence of acute exacerbation of IP within 1 year after treatment initiation, overall survival, progression-free survival, objective response rate and safety. As a translational research, we will perform analysis of TMB, somatic mutations and MSI from tumour samples. Legal entity responsible for the studyThoracic Oncology Research Group (TORG). FundingChugai Pharmaceutical Co., Ltd. DisclosureS. Ikeda: Honoraria (self), Research grant / Funding (institution): Chugai Pharmaceutical; Honoraria (self): Boehringer Ingelheim; Honoraria (self): AstraZeneca; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Ono Pharmaceutical. T. Kato: Honoraria (self), Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Astellas; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self): Boehringer Ingelheim; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (self): Chugai Pharmaceutical; Honoraria (self), Research grant / Funding (self): Eli Lilly; Research grant / Funding (institution): Kyorin Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Kyowa Hakko Kirin; Honoraria (self), Research grant / Funding (institution): Merck Serono; Honoraria (self), Research grant / Funding (institution): Merck Sharp and Dohme; Honoraria (self): Nitto Denko; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self): Quintiles; Research grant / Funding (institution): Regeneron; Honoraria (self): Sumitomo Dainippon Pharma; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self): Takeda Pharmaceutical; Honoraria (self): F. Hoffmann-La Roche. H. Kenmotsu: Honoraria (self), Research grant / Funding (institution): Chugai Pharmaceutical; Honoraria (self): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self): Eli Lilly ; Honoraria (self): Kyowa Hakko Kirin; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Merck Sharp and Dohme; Honoraria (self): Novartis Pharma; Honoraria (self): Daiichi-Sankyo; Honoraria (self), Research grant / Funding (institution): AstraZeneca. T. Ogura: Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self): Meiji Seika Pharma; Honoraria (self): Shionogi Pharmaceutical; Honoraria (self): Toray; Honoraria (self): AstraZeneca; Honoraria (self): Eisai; Honoraria (self): Astellas Pharma; Honoraria (self): Kyorin Pharmaceutical; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Actelion Pharmaceuticals; Honoraria (self): Novartis. S. Iwasawa: Honoraria (self), Research grant / Funding (institution): Chugai Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self): AstraZeneca. T. Iwasawa: Honoraria (self): Ono pharmaceutical; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Shionogi. T. Yamanaka: Honoraria (self), Research grant / Funding (institution): Takeda Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Chugai Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Daiichi-Sankyo; Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Eli Lilly; Honoraria (self): Pfizer; Honoraria (self): Sysmex; Honoraria (self): Huya Biosciences; Honoraria (self): Gilead Sciences. H. Okamoto: Research grant / Funding (institution): Chugai Pharmaceutical; Research grant / Funding (institution): Takeda Pharmaceutical; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Merck Sharp and Dohme; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Taiho pharmaceutical; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Daiichi Sankyo. All other authors have declared no conflicts of interest.

Real-World Data Of Osimertinib In Patients With Pretreated Non-Small Cell Lung Cancer: A Retrospective Study.

PurposeOsimertinib is an oral, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeted for both EGFR sensitizing mutations and T790M resistance mutation in patients with non-small-cell lung cancer (NSCLC). We assessed efficacy and safety of osimertinib in patients with pretreated NSCLC in a real-world setting.Patients and methodsNinety-four patients with advanced NSCLC who received osimertinib after progression of prior EGFR-TKIs or chemotherapy treatments were retrospectively collected.ResultsIn patients evaluable for response analysis (n = 91), overall objective response rate (ORR) was 47.3%, and disease control rate (DCR) was 90.1%. Median duration of response (DoR) in responding patients was 12.5 months (95% confidence interval [CI], 10.7 to 14.3). Median progression-free survival (PFS) was 8.5 months (95% CI, 7.4 to 9.6) in 2nd line group, 9.1 months (95% CI, 6.6 to 11.6) in ≥3rd line group, and 8.6 months (95% CI, 7.2 to 10.0) in overall population. For subgroup analysis, DCR and median PFS were 91.9% and 8.6 months (95% CI, 7.2 to 10.0) in patients with detectable T790M mutation, respectively, while 80.0% and 3.2 months (95% CI, 0.5 to 5.9) for those without. Median PFS was significantly longer for T790M-positive patients co-occurring with exon19del than with L858R (17.9 months vs 7.3 months; P<0.001). Among 45 patients with metastases to the central nervous system (CNS), median systemic PFS was 8.8 months (95% CI, 6.9 to 10.7), while intracranial time to progression (iTTP) was not reached. Safety profile was acceptable, no adverse events (AEs) related deaths was observed.ConclusionOsimertinib was highly active in patients with pretreated advanced NSCLC who harbored EGFR T790M mutation, with manageable side-effects.

Italian Cohort of Nivolumab Expanded Access Program in Squamous Non-Small Cell Lung Cancer: Results from a Real-World Population.

Nivolumab has shown a survival benefit compared with docetaxel as second-line treatment for patients with previously treated advanced squamous non-small cell lung cancer (NSCLC) in a randomized phase III trial. The experiences of patients and physicians in routine clinical practice are often different from those in a controlled clinical trial setting. We present data from the entire Italian cohort of patients with squamous NSCLC enrolled in a worldwide nivolumab NSCLC expanded access program. Patients with pretreated advanced squamous NSCLC received nivolumab 3 mg/kg every 2 weeks for up to 24 months. Safety was monitored throughout; efficacy data collected included objective tumor response, date of progression, and survival information. The Italian cohort comprised 371 patients who received at least one dose of nivolumab. In the overall population, the objective response rate (ORR) was 18%, the disease control rate (DCR) was 47%, and median overall survival (OS) was 7.9 months (95% confidence interval 6.2-9.6). In subgroup analyses, ORR, DCR, and median OS were, respectively, 17%, 48%, and 9.1 months in patients previously treated with two or more lines of therapy (n = 209) and 8%, 40%, and 10.0 months in patients treated beyond disease progression (n = 65). In the overall population, the rate of any-grade and grade 3-4 adverse events was 29% and 6%, respectively. Treatment-related adverse events led to treatment discontinuation in 14 patients (5%). There were no treatment-related deaths. To date, this report represents the most extensive clinical experience with nivolumab in advanced squamous NSCLC in current practice outside the controlled clinical trial setting. These data suggest that the efficacy and safety profiles of nivolumab in a broad, real-world setting are consistent with those obtained in clinical trials. Nivolumab is approved in the U.S. and Europe for the treatment of advanced non-small cell lung cancer (NSCLC) after failure of prior platinum-based chemotherapy. In this cohort of Italian patients with previously treated, advanced squamous NSCLC treated in a real-world setting as part of the nivolumab expanded access program, the efficacy and safety of nivolumab was consistent with that previously reported in nivolumab clinical trials.

Radiotherapy is an independent prognostic marker of favorable prognosis in non-small cell lung cancer patients after treatment with the immune checkpoint inhibitor, nivolumab.

BackgroundIt remains unclear why radiation clinically provides a synergistic effect when combined with immune checkpoint inhibitors such as nivolumab. The purpose of our study was to retrospectively evaluate whether the therapeutic efficacy of nivolumab is improved as a result of a history of radiotherapy (RT) in patients with previously treated advanced non‐small cell lung cancer (NSCLC).MethodsFrom February 2016 to December 2017, 124 consecutive patients were administered nivolumab for pretreated advanced NSCLC. The patients were divided into RT and non‐RT groups.ResultsSixty‐six (53%) of the 124 patients had been administered RT before the initiation of nivolumab, 52 (42%) received extracranial RT, and 40 (32%) were treated with thoracic RT. The median number of nivolumab cycles was 4 (range: 1–43). The overall response rate (ORR) and disease control rate (DCR) of nivolumab in all patients were 28.0% and 58.4%, respectively. The ORR (36.4%) was significantly higher in patients who had received previous RT than in patients who had not received any RT (19%). The therapeutic efficacy of nivolumab was particularly noteworthy in patients with non‐adenocarcinoma and squamous cell carcinoma histology administered extracranial RT, with ORRs of 48.3% and 52.6%, and DCRs of 87.1% and 84.2%, respectively.ConclusionPrevious RT was an independent prognostic marker of favorable prognosis after nivolumab administration and improved the response rate to nivolumab treatment. Previous RT was clinically identified to have a synergistic effect with nivolumab treatment, increasing the response rate and improving the outcome of patients with advanced NSCLC.

Efficacy and Safety of Addition of Anti-PD1 to Chemotherapy in Treatment of Non-Small Cell Lung Cancer.

Patients with previously treated non-small-cell lung cancer (NSCLC) have limited treatment options. A novel treatment based on programmed death 1 (PD-1)/programed death ligand 1 (PD-L1) inhibitors has emerged as promising therapeutic options for advanced NSCLC. We assessed oncological outcomes of PD-L1 antibody versus docetaxel in previously treated NSCLC. The purpose of this meta-analysis was to analyse the oncological outcomes of anti-PD1 to chemotherapy in the treatment of non-small-cell lung cancer. Overall survival (OR=0.68,95%CI=0.61-0.75, P<0.00001) and progression-free survival (OR=0.84,95%CI=0.77-0.92, P=0.0002) were longer with anti-PD1 than with docetaxel in NSCLC. Anti-PD1 was associated with even greater objective response rate than docetaxel (OR=1.61,95%CI=1.16-2.24, P=0.004). Treatment-related adverse events of grade 3-5 did favor anti-PD1 over docetaxel (OR=0.21,95%CI=0.10-0.42, P<0.00001). Among patients with advanced NSCLC, we found that there was a superior survival benefit and with a favorable safety profile with anti-PD1 than with docetaxel. More large-scale randomized controlled trials are needed to identify relevant biomarkers that have an effect on predicting the population that would most likely benefit from PD-1/PD-L1 for pretreated advanced NSCLC patients.

Analysis of Pleiotropic Effects of Nivolumab in Pretreated Advanced or Recurrent Non-small Cell Lung Cancer Cases.

Nivolumab is an immune checkpoint inhibitor for advanced non-small cell lung cancer (NSCLC). We investigated the safety and efficacy of nivolumab by analyzing the response factor, adverse effects (AE), and the post-treatment condition of pretreated advanced or recurrent NSCLC patients. Nivolumab (3 mg/kg) was administered to 79 pre-treated NSCLC patients from December 2015 to January 2018. Nivolumab efficacy and AE were assessed using the Response Evaluation Criteria in Solid Tumors and the Common Terminology Criteria, respectively. Progression-free survival (PFS) was significantly prolonged in cases where the therapeutic effect of the pretreatment was a partial response (p=0.0004). Five cases (6.3%) experienced grade 3-4 AEs. PFS was significantly prolonged in the skin rash group versus the non-skin rash group, and in patients where nivolumab treatment was discontinued. Long-term survival was observed in patients with skin rash. Therapeutic effect of nivolumab immediately following its administration appears to be favorable for survival.

Pembrolizumab in combination with ipilimumab as second-line or later therapy for advanced non–small-cell lung cancer: KEYNOTE-021 cohorts D and H

ObjectivesCombination immunotherapy may result in improved antitumor activity compared with single-agent treatment. We report results from dose-finding and dose-expansion cohorts of the phase 1/2 KEYNOTE-021 study that evaluated combination therapy with anti‒programmed death 1 (PD-1) antibody pembrolizumab plus anti‒cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody ipilimumab in patients with previously treated advanced non–small-cell lung cancer (NSCLC). Materials and methodsEligibility criteria stipulated histologically/cytologically confirmed advanced NSCLC and treatment failure on ≥1 prior systemic therapy (platinum-based chemotherapy or targeted therapy for patients with EGFR/ALK aberrations). In the dose-finding cohort, patients initially received pembrolizumab 10 mg/kg plus ipilimumab 1 or 3 mg/kg once every 3 weeks for 4 cycles followed by pembrolizumab 10 mg/kg monotherapy for up to 2 years. Based on emerging published data, subsequent patients received pembrolizumab 2 mg/kg plus ipilimumab 1 mg/kg. Objective response rate (ORR; primary efficacy endpoint) was assessed per RECIST version 1.1 by blinded, independent central review. Phase 2 hypothesis that ORR would be greater than the 20% rate for historical controls was evaluated using the exact binomial test. ResultsFifty-one patients were enrolled; 71% received ≥2 prior lines of therapy. No dose-limiting toxicities occurred at any dose level. Among patients who received pembrolizumab 2 mg/kg plus ipilimumab 1 mg/kg (n = 44), ORR was 30% (95% CI, 17%–45%), but not statistically significantly >20% (P = 0.0858). Median progression-free survival in this group was 4.1 (95% CI, 1.4–5.8) months; median overall survival was 10.9 (95% CI, 6.1–23.7) months. With pembrolizumab 2 mg/kg plus ipilimumab 1 mg/kg, incidences of treatment-related adverse events, grade 3–5 treatment-related adverse events, and immune-mediated adverse events and infusion reactions were 64%, 29%, and 42%, respectively. ConclusionsIn patients with heavily pretreated advanced NSCLC, pembrolizumab plus ipilimumab showed evidence of antitumor activity, but was associated with meaningful toxicity.

Immune Checkpoint Inhibitor Nivolumab and Radiotherapy in Pretreated Lung Cancer Patients: Efficacy and Safety of Combination.

In the last decade, the discovery of immune checkpoint inhibitors such as the PD-1 inhibitor, nivolumab, has revolutionized the treatment of advanced non-small cell lung cancer (NSCLC). Concurrent radiotherapy (RT) is of particular interest in showing the potential role of the combination. The purpose of this study was to retrospectively evaluate the addition of RT to an immune checkpoint inhibitor, nivolumab, with regard to activity and feasibility in pretreated, advanced, or metastatic lung cancer patients at our center. We retrospectively identified 35 consecutive patients (30 men and 5 women), who received nivolumab for pretreated NSCLC, between March 2015 to December 2016. Fifteen received hypofractionated RT as a palliative measure, and, in these patients, nivolumab was administered at an interval of at least 1 week from the end of RT. The median age was 69 years, and 23 patients (65.7%) had an Eastern Cooperative Oncology Group (ECOG) score of 0 to 1. All patients had previously received at least 1 systemic regimen, and, for only 3 (8.6%), nivolumab was a third-line treatment. The 2 treatment arms, RT-nivolumab and only-nivolumab, were well matched for baseline characteristics. At a median follow-up of 7.4 months, the 1-year overall survival rates were 57.8% for patients treated with RT-nivolumab and 27.4% for patients treated with only-nivolumab (P=0.043). The 1-year progression-free survival in the RT-nivolumab group was 57.8% and 20.6% in the only-nivolumab group (P=0.040). No difference in adverse events was detected. In conclusion, RT and nivolumab can be combined, obtaining a benefit in overall survival and progression-free survival, without an increase in acute toxicities in pretreated advanced NSCLC patients. Prospective studies are needed to confirm these results.

Afatinib in heavily pretreated advanced NSCLC patients who progressed following prior gefitinib or erlotinib: Compassionate use program in Korea

IntroductionAfatinib, an irreversible ErbB family blocker, approved for first-line treatment of epidermal growth factor receptor (EGFR) mutated advanced non-small cell lung cancer (NSCLC). This study investigated experience of afatinib within a compassionate use program (CUP). MethodsThe afatinib CUP was an open-label, multicenter, single-arm program in Korea. We enrolled patients with stage IV NSCLC and who had received at least one line of previous cytotoxic chemotherapy and previous EGFR TKI treatment with either an EGFR mutation or documented clinical benefit. The starting dose of afatinib was 50 mg once daily. ResultsFrom August 2011 to September 2014, 332 patients received at least one dose of afatinib. Most patients were registered in the CUP for fourth- or fifth-line treatment with afatinib. Adverse events (AEs) occurred in 98.1% of patients, including 29.8% with serious AEs. The most common AEs (all grades) were diarrhea (90.1%) and skin rash (62.0%). Dose reductions occurred in 60.5% of patients and discontinuations due to AEs were reported in 11.1% of patients. The response rate and median time to treatment failure (TTF) were 27.4% and 3.3 months (CI 95%, 2.8–3.8 months), respectively, in this highly pretreated population. In subgroup analysis, ECOG PS 0 or 1 and immediate pretreatment with pemetrexed monotherapy or a platinum doublet were associated with a longer TTF for afatinib. ConclusionsNo additional or unexpected safety concerns were observed, and afatinib demonstrated moderate antitumor activity in advanced NSCLC patients with acquired resistance to gefitinib or erlotinib in a real-world setting.