Pretreated Non-small Cell Lung Cancer Research Articles

Real-world comparative effectiveness of sotorasib versus docetaxel in second line and beyond among patients with advanced non-small cell lung cancer (NSCLC)

ObjectivesTo evaluate the comparative effectiveness of sotorasib monotherapy versus docetaxel as monotherapy or combination therapy in patients with pretreated KRAS G12C-mutated advanced NSCLC in the real-world. MethodsA US-based electronic health record–derived de-identified database was used in this study. Patients with pretreated KRAS G12C-mutated advanced NSCLC who initiated sotorasib between May 28, 2021, and September 30, 2022, and docetaxel between January 1, 2019, and September 30, 2022 (to enhance sample size), were included, with a minimum of 12-month opportunity for follow-up. Treatment groups were balanced via overlap weighting propensity score methods. Median OS in the 2L and 2L+ settings were calculated using Kaplan-Meier estimates. Hazard ratios (HRs) were estimated via Cox proportional hazard models. ResultsOverall, the clinical characteristics in sotorasib and docetaxel cohorts were balanced after propensity score weighting. At baseline, most patients were > 65 years of age, had ECOG performance status of 0–1, were from the community practice setting, had advanced stage at initial diagnosis, and had prior anti-PD-(L)1 treatment and/or platinum-based chemotherapy. In the 2L setting, the median OS (95 % CI) for sotorasib (N=102) and docetaxel (N=58) patients was 10.2 (7.6–16.3) and 6.0 (4.2–11.0) months, respectively, with a corresponding mortality HR (95 % CI) of 0.62 (0.41–0.93). In the 2L+ setting, the median OS (95 % CI) for sotorasib (N=164) and docetaxel (N=116) was 10.2 (8.0–14.6) and 7.2 (5.1–10.6) months, respectively, with a corresponding mortality HR (95 % CI) of 0.65 (0.49–0.87). In patients with prior anti-PD-(L)1 treatment, the mortality HR (95 % CI) in the sotorasib group versus docetaxel was 0.61 (0.39–0.94) and 0.65 (0.48–0.89) in the 2L and 2L+ settings, respectively. Findings from other subgroups were consistent with the primary analyses. ConclusionIn this real-world comparative analysis of patients with pretreated KRAS G12C-mutated advanced NSCLC, sotorasib monotherapy demonstrated a longer median OS compared to docetaxel monotherapy or combination therapy.

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.

Unrealistic expectations and disclosure of incurability in patients with non-small cell lung cancer.

Determining whether patients' unrealistic expectations of chemotherapy as a cure were associated with their perception of the disclosure of incurability. This prospective study included consecutive patients with pretreated non-small cell lung cancer from four study sites. Patients and their oncologists were asked whether they perceived the disclosure of cancer incurability. Patients were also asked if they thought that chemotherapy was curative. We followed up on whether the deceased patients received specialized palliative care 14 months after their last enrollment. Multiple regression analyses were conducted to examine the association between the expectation of chemotherapy as a cure and patient/oncologist-reported perceptions of the disclosure of incurability. We analyzed 200 patients, 77 (38.5%) of whom had unrealistic expectations of a cure. Based on patients' perceptions, incurability was disclosed to 138 (69.0%) patients, and based on their oncologists' perceptions, incurability was disclosed to 185 (92.5%) patients (patient/oncologist agreements, κ = 0.19). Patients without a perception of the oncologist's disclosure of incurability-regardless of their oncologist's perception-were more likely to have unrealistic expectations of a cure than patients for whom both patient and oncologist perceptions were present. Patients who had unrealistic expectations of chemotherapy as a cure were shown to be significantly less likely to have received specialized palliative care, after adjusting for covariates (adjusted OR, 0.45; 95% CI, 0.23-0.91; p = .027). Oncologists' disclosure of incurability was not fully recognized by patients, and expectations of chemotherapy as a cure were associated with patients' perception of the disclosure of incurability.

A multinational pivotal study of sunvozertinib in platinum pretreated non-small cell lung cancer with EGFR exon 20 insertion mutations: Primary analysis of WU-KONG1 study.

8513 Background: A multinational pivotal study WU-KONG1 (NCT03974022) has been conducted to assess sunvozertinib (DZD9008) in pre-treated non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations (exon20ins). Here we report the results of primary analysis. Methods: WU-KONG1 Part B is a phase 2, multinational pivotal study to assess the antitumor efficacy of sunvozertinib at two dose levels, 200 mg and 300 mg, in platinum pre-treated NSCLC patients with EGFR exon20ins. Eligible patients were randomized at the ratio of 1:1 to receive 200 mg or 300 mg sunvozertinib once daily until discontinuation criteria were met. Randomization was stratified by brain metastasis at baseline and number of regimens of prior systemic anti-cancer therapy. The primary endpoint was Independent Review Committee (IRC) assessed objective response rate (ORR) (per RECIST v1.1) and key secondary endpoint included IRC assessed duration of response (DoR). Results: As of January 4, 2024, a total of 184 patients were randomized to receive sunvozertinib treatment at 200 mg or 300 mg. Patients who met the predefined criteria for efficacy analysis were included in the primary analysis. The majority of patients (96.0%) had metastatic diseases, 60.7% had ECOG PS of 1, and 23.7% had baseline brain metastasis. All patients received prior platinum-based chemotherapy for advanced NSCLC, and 43.4% and 13.3% had prior onco-immunotherapy or amivantamab treatment. Per IRC assessment, the best ORR was 54.3% (41.0% confirmed and 5.8% pending confirmation). Confirmed complete response (CR) was achieved in 2.9% patients. The disease control rate (including CR, PR and stable disease) was 90.8%. The primary endpoint met its predefined target, with statistical significance. Tumor response was observed in patients with baseline brain metastasis, different demographics and EGFR exon20ins subtypes. With median follow-up time of 5.5 months for responders, the duration of response has not been reached, with 74.6% responders still responding. The PFS data are not mature with approximately 6-month follow-up. Safety findings were similar to previously reported results of sunvozertinib in other clinical studies. The most common drug-related TEAEs included diarrhea, skin rash and CPK increase. The majority of the TEAEs were CTCAE grade 1 or 2 and clinically manageable. Conclusions: In this primary analysis of WU-KONG1 multinational pivotal study, sunvozertinib demonstrated promising antitumor efficacy in platinum pre-treated NSCLC with EGFR exon20ins, with a tolerable safety profile. The updated data will be presented at the meeting. Clinical trial information: NCT03974022 .

Phase I summary of the HB0025 efficacy and safety to the heavily pretreated non-small cell lung cancer (NSCLC) population.

e14600 Background: HB0025 is a recombinant humanized bispecific molecule built on IgG1 that targets the human programmed death ligand 1 (PD-L1) and vascular endothelial growth factor (VEGF, VEGF-A, VEGF165). Here we present the NSCLC results in Phase 1 study. Methods: This ongoing, open-label, multicenter, dose escalation and dose expansion, phase 1 trial to evaluate the safety and efficacy of HB0025 for pts with advanced solid tumors. HB0025 is administered intravenously every 14 days (Q2W). Response was evaluated by RECIST v.1.1 every 8 weeks. Results: As of Dec 25, 2023, 12 (7M/5F) NSCLC pts have received HB0025 at doses of 3mg/kg (n=1), 6mg/kg (n=2), 10mg/kg (n=2), 12mg/kg (n=1), 20mg/kg (n=5), 30mg/kg (n=1). Overall, the median age was 61.5 years, the median number of prior treatment lines was 4. The histologic types include squamous cell (Sq)-NSCLC (2 pts) without EGFR/ALK mutation and non- squamous cell (Nonsq)-NSCLC (10 pts), among of Nonsq-NSCLC 9 pts carrying EGFR/ALK mutation. The 3 pts with EGFR/ALK wild-type gene fail to prior anti-PD-1 treatment, 9 pts with EGFR/ALK gene mutation fail to prior TKI therapy. Among the 12 pts having imaging tumor assessment, the ORR was 25% and DCR was 66.7%, which included 3 partial responses (PR) ,5 stable disease (SD), and 4 progressive disease (PD) according to RECIST v1.1.For the 2 Sq-NSCLC pts, one pt achieved PR with 3mg/kg HB0025 treatment, the other pt achieved SD. For the10 Nonsq-NSCLC pts, there were 2 PR (20mg/kg and 30mg/kg treatment, respectively), 4 SD and 4 PD. Till the report date, the PR status and HB0025 treatment are ongoing to 3 PR pts, which includes 1 Sq-NSCLC pt, and 2 Nonsq-NSCLC pts which one pt doesn’t carry EGFR/ALK mutation. The Sq-NSCLC pt whose maximum tumor regression is 60% achieves PR after 4 cycles of treatment, and the duration of response (DOR) is more than 22 months. The one Nonsq-NSCLC pt whose maximum tumor regression is 74% achieves PR after 2 cycles of treatment, and the DOR is more than 11 months. The other Nonsq-NSCLC pt whose tumor regression is 32% achieves PR after 4 cycles of treatment, and the DOR is more than 2 months. Among the 5 SD pts, 1 Sq-NSCLC pt’s progression-free survival (PFS) is more than 14 months and continusous, 2 Nonsq-NSCLC pts’ PFS is more than 6 months and ongoing. For the 12 pts, 11 pts (91.7%) experienced a treatment related adverse events (TRAEs). The most common TRAEs included proteinuria (50%, 6/12), lymphocyte count decrease (50%, 6/12), blood bilirubin increased (33.3%, 4/12), and blood pressure increased (33.3%, 4/12). TRAEs ≥ grade 3 occurred in 2 (16.7%) pts. No TRAE leading to discontinuation and death. Conclusions: HB0025 monotherapy showed an acceptable safety profile and promising anti-tumor activity for prior heavily treated NSCLC, no matter in TKI-resistant population with EGFR/ALK mutation or population failed to anti-PD-1 treatment. Now Phase II studies of combination chemotherapy are ongoing. Clinical trial information: NCT04678908 .

The efficiency and safety of temozolomide and PD-1/L1 inhibitors in pretreated NSCLC with brain metastasis: a retrospective cohort

ObjectivePrevious research has shown that both temozolomide (TMZ) and PD-1/L1 inhibitors (PD-1/L1) alone exhibit certain potential in the treatment of non-small cell lung cancer (NSCLC) with brain metastases (BM), in this study, we will explore combining the two in order to seek new effective treatment options for NSCLC with BM.Material and methodsDuring 2021.1 to 2023.12, we collected the date of these pretreated-NSCLC with BM who accept the treatment of TMZ and PD-1/L1, the objective response ratio (ORR), progression-free survival (PFS) and overall survival (OS) were set as the primary endpoint, meanwhile, the toxicity of such regimen was also recorded.ResultsAbout 42 patients are enrolled, our primary analysis demonstrated that the ORR of such regimen toward NSCLC with BM was 26.19%, with Approximate intracranial and extracranial lesion ORR was 6% and 20% respectively, the DCR was about 64.29%, the mean PFS and OS was about 4 m and 8.5 m. Further analysis indicated that the efficiency correlated with the diagnosis-Specific Graded Prognostic Assessment (ds-GPA) score. Moreover, the toxicity can also be tolerated, indicating the application potential of such regimen against NSCLC with BM.ConclusionsOur results exhibited that with tolerated toxicity, the combination of TMZ and PD-1/L1 shows promising efficiency against NSCLC with BM, this would be of great significance for the treatment of NSCLC with brain metastasis. However, due to the limitation of sample and retrospective property, the real value of such regimen needed to be further confirmed in the future.

Abstract CT248: Trastuzumab deruxtecan (T-DXd) in Chinese patients (pts) with previously treated HER2 mutant non-small cell lung cancer (NSCLC): primary analysis from the Phase 2 DESTINY-Lung05 (DL-05) trial

Abstract Background: In China, non-approved therapies are used for pts with HER2 (ERBB2) mutant (HER2m) NSCLC. In DESTINY-Lung02 (DL-02), T-DXd 5.4 mg/kg showed clinical benefit with an acceptable and manageable safety profile in pts with pretreated HER2m metastatic NSCLC. DL-02 did not include any Chinese pts. We report the primary analysis of T-DXd in Chinese pts with pretreated HER2m metastatic NSCLC. Methods: In this open-label, single-arm, Phase 2 trial (NCT05246514), Chinese pts with HER2m (locally or centrally confirmed activating HER2 exon 19 or 20 mutation) metastatic non-squamous NSCLC with disease progression on or after ≥1 prior anticancer therapy (no prior HER2-directed) received T-DXd 5.4 mg/kg IV once every 3 weeks. The primary endpoint was confirmed objective response rate (ORR) by independent central review (ICR). Secondary endpoints included investigator-assessed (INV) confirmed ORR; ICR and INV duration of response, disease control rate, progression-free survival, and safety. Results: At data cutoff (September 23, 2023), 72 pts with HER2m NSCLC received T-DXd 5.4 mg/kg (full analysis set). Median T-DXd exposure was 7.9 (0.7-13.5) months. Pt characteristics and efficacy data are in the table. 71 pts had drug-related adverse events (AEs), of which 51.4% were grade (G) ≥3. Most common G≥3 AEs by grouped term: neutropenia (26.4%), thrombocytopenia (18.1%), and leukopenia (11.1%). Drug-related AEs leading to discontinuations occurred in 2 (2.8%) pts. 17 (23.6%) pts had serious AEs, with no INV-adjudicated G5. Centrally adjudicated drug-related ILD/pneumonitis occurred in 7 (9.7%) pts (n=6 G2; n=1 G5). Conclusion: T-DXd 5.4 mg/kg demonstrated clinically meaningful and durable responses and a manageable safety profile in Chinese pts with HER2m metastatic NSCLC. Results were consistent with DL-02 and the known safety profile of T-DXd, supporting its use in this pt population. TABLE 1. NAND Pt characteristics and efficacy data Full analysis set* N=72 Median age, years (min, max) 57.0 (34, 76) Female, n (%) 41 (56.9) Former smoker, n (%) 22 (30.6) Prior lines of therapy, n (%) 1 30 (41.7) ≥2 42 (58.3) Most common prior treatment modalities, n (%) Cytotoxic chemotherapy 67 (93.1) Platinum chemotherapy 65 (90.3) Immunotherapy 49 (68.1) Antiangiogenic therapy 49 (68.1) Median duration of follow up, months (range) 9.8 (1.0–14.0) Efficacy ICR INV Confirmed ORR, % (95% CI) 58.3 (46.1, 69.8) 58.3 (46.1, 69.8) Median DOR, months (95% CI) NE (6.1, NE) 9.0 (7.2, NE) DCR, % (95% CI) 91.7 (82.7, 96.9) 93.1 (84.5, 97.7) Median PFS, months (95% CI) NE (7.2, NE) 10.8 (7.2, NE) 12-month PFS rate, % (95% CI) 55.1 (41.4, 66.8) 39.7 (19.5, 59.4) *Pts with HERm assessed by central testing. CI, confidence interval; DCR, disease control rate; DOR, duration of response; HER2m, HER2 mutant; ICR, independent central review; INV, investigator assessed; NE, not estimable; ORR, objective response rate; PFS, progression-free survival; pts, patients Citation Format: Ying Cheng, Lin Wu, Yong Fang, Yun Fan, Xingya Li, Mingjun Zhang, Yan Yu, Yu Yao, Ruilian Xu, Jun Guo, Huaping Yang, Jian Fang, Feng Luo, Xuhong Min, Ke-jing Tang, Jie Hu, Yunru Chen, Rui Mao, Victor Zhang, Dairong Li. Trastuzumab deruxtecan (T-DXd) in Chinese patients (pts) with previously treated HER2 mutant non-small cell lung cancer (NSCLC): primary analysis from the Phase 2 DESTINY-Lung05 (DL-05) trial [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 CT248.

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.

The Efficiency and Safety of Triple-Drug Combination of Albumin-Bound Paclitaxel, Anlotinib and PD-1/L1 Inhibitors in the 2nd or Above Line of Advanced NSCLC: A Retrospective Cohort Study.

Existing research data indicates that albumin-bound paclitaxel (nab-ptx), anlotinib, and PD-1/L1 inhibitors have individually shown efficacy in second-line and subsequent treatments for advanced non-small cell lung cancer (NSCLC). This study seeks to investigate the potential of an optimized treatment regimen in this context by combining these three drugs and evaluating both efficacy and safety outcomes. Between January 2020 and January 2022, we collected data from pre-treated advanced NSCLC patients who received a combination therapy of nab-ptx, anlotinib, and PD-1/L1 inhibitors as a second-line or later treatment. The primary endpoints for the study included the objective response rate (ORR), progression-free survival (PFS), disease control rate (DCR) and overall survival (OS), while adverse events (AEs) were also recorded. Our findings revealed that the ORR of this regimen in pretreated NSCLC patients was 35.71%, with mean PFS of 5.0 months and mean OS of 10.0 months. Further analysis suggested correlations between the efficacy of the regimen and factors such as PD-L1 expression levels, the occurrence of certain types of adverse events, and the status of NK cell activity. Additionally, the tolerable toxicity profile of this regimen indicates its potential applicability in the treatment of pretreated advanced NSCLC. Our study displayed that triple-drug combination of nab-ptx, anlotinib and PD-1/L1 inhibitors showed promising efficiency and tolerated cytotoxicity in the 2nd or above line treatment of advanced NSCLC, indicating the potential of such regimen as an important option for second-line treatment of advanced NSCLC. However, due to limitations in patient numbers, its actual clinical value awaits further research confirmation.

Sunvozertinib for patients in China with platinum-pretreated locally advanced or metastatic non-small-cell lung cancer and EGFR exon 20 insertion mutation (WU-KONG6): single-arm, open-label, multicentre, phase 2 trial

Sunvozertinib is an oral, irreversible, and selective tyrosine kinase inhibitor that has a favourable safety profile and encouraging antitumour activity, as shown in phase 1 studies of patients with heavily pretreated non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutation (exon20ins). We aimed to assess the antitumour efficacy of sunvozertinib in patients with platinum-pretreated locally advanced or metastatic NSCLC with EGFR exon20ins. WU-KONG6 is a single-group, open-label, multicentre phase 2 trial of sunvozertinib monotherapy, conducted across 37 medical centres in China. We enrolled adult patients with pathologically or cytologically confirmed locally advanced or metastatic NSCLC whose tumour tissue carried an EGFR exon20ins mutation. All patients had received at least one line of previous systemic therapy, with at least one line containing platinum-based chemotherapy. The primary endpoint was objective response rate (ORR), as assessed by the independent review committee. The ORR was defined as the percentage of patients who achieved complete or partial response, confirmed by two separate assessments with at least 4-week time interval, until disease progression or initiation of any new anti-cancer therapy. Enrolled patients received sunvozertinib 300 mg once daily until meeting discontinuation criteria per the protocol. Patients who received at least one dose of treatment and were evaluable for efficacy analysis were included in the primary analysis, and all patients who received at least one dose of treatment were included in the safety analysis. This study is registered with ChinaDrugTrials.org, CTR20211009, and ClinicalTrials.gov, NCT05712902, and efficacy and safety follow-up are ongoing. Between July 19, 2021, and May 6, 2022, 104 patients were enrolled. At data cutoff (Oct 17, 2022), the last enrolled patient had been followed up for about 6 months. Among 97 patients evaluable for efficacy analysis, 59 (61%) patients achieved tumour response, with a confirmed ORR of 61% (95% CI 50-71). All tumour responses were partial responses. Tumour responses were observed irrespective of age, sex, smoking history, EGFR exon20ins subtypes, brain metastasis at baseline, previous lines of therapy, and history of onco-immunotherapy. In total, 19 death events occurred over a median follow-up period of 7·6 months (IQR 6·1-9·4). Sunvozertinib was well tolerated at 300 mg once daily. The most common grade 3 or worse treatment-related adverse events were blood creatine phosphokinase increased (18 [17%] of 104), diarrhoea (eight [8%]), and anaemia (six [6%]). The most common serious treatment-related adverse events were interstitial lung disease (five [5%] of 104), anaemia (three [3%]), vomiting (two [2%]), nausea (two [2%]) and pneumonia (two [2%]). In this phase 2 study, sunvozertinib demonstrated antitumour efficacy in patients with platinum-based chemotherapy pretreated NSCLC with EGFR exon20ins, with a manageable safety profile. A multinational randomised, phase 3 study of sunvozertinib versus platinum-doublet chemotherapy in EGFR exon20ins NSCLC is ongoing (NCT05668988). Dizal Pharmaceutical.

High PD-L1 Expression Correlates with an Immunosuppressive Tumour Immune Microenvironment and Worse Prognosis in ALK-Rearranged Non-Small Cell Lung Cancer.

High tumour programmed cell death-ligand 1 (PD-L1) expression is associated with poor progression-free survival (PFS) after tyrosine kinase inhibitor (TKI) therapy in ALK-rearranged non-small cell lung cancer (NSCLC). However, the characteristics of the tumour microenvironment (TME) and their prognostic values in ALK-rearranged NSCLC are unknown. Here, we collected tumour tissues from pretreated ALK-rearranged NSCLC patients, immunohistochemical staining was used to assess PD-L1 expression, and tumour-infiltrating immune cells were determined via multiplex immunofluorescence staining (mIF). Our data showed that the median values of PFS for the high PD-L1 group and low PD-L1 group who received ALK-TKI treatment were 4.4 and 16.4 months, respectively (p = 0.008). The median overall survival (OS) of the two groups was 24.0 months and not reached, respectively (p = 0.021). Via univariate and multivariate analyses, a high PD-L1 expression and a worse ECOG PS were determined to be independent prognostic factors of OS (HR = 3.35, 95% CI: 1.23-9.11, p = 0.018; HR = 6.42, 95% CI: 1.45-28.44, p = 0.014, respectively). In addition, the high PD-L1 group had increased Tregs and exhausted CD8+ T cells in both the tumour and stroma (all p < 0.05). High PD-L1 expression was an adverse predictive and prognostic biomarker for ALK-rearranged NSCLC. The characteristics of the TME in patients with high PD-L1 expression were shown to have an immunosuppressive status.

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 .

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 .

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 &lt; 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&lt;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 .

Mirzotamab clezutoclax as monotherapy and in combination with taxane therapy in relapsed/refractory solid tumors: Dose expansion results.

3027 Background: Mirzotamab clezutoclax (ABBV-155; Mirzo-C) is a first-in-class antibody-drug conjugate with three components: an anti–B7-H3 monoclonal antibody, a solubilizing linker, and a BCL-XL inhibitor payload. By specific targeting of BCL-XL, synergy with other anticancer agents was observed in preclinical models. When combined with a taxane, clinical antitumor activity was reported in relapsed and/or refractory (R/R) solid tumors during the dose escalation phase of an ongoing Phase 1, open-label study (NCT03595059). Methods: In the dose expansion phase of the Phase 1 study, patients were treated as follows: (i) R/R small cell lung cancer (SCLC) with Mirzo-C monotherapy, (ii) non-small cell lung cancer (NSCLC) with Mirzo-C + docetaxel, and (iii) hormone positive, Her2 negative, post–CDK4/6 inhibitor breast cancer (BrCa) with Mirzo-C + paclitaxel. Mirzo-C was administered at the recommended Phase 2 dose determined at dose escalation. Primary objectives were safety and overall response rate (ORR). Results: As of November 18, 2022, 78 patients were enrolled (SCLC n=14; NSCLC n=36; BrCa n=28). The median (range) follow-up was 2.0 (0.6–9.1) months for the SCLC cohort, 4.9 (0.6–8.5) for NSCLC, and 10.4 (0.8–13.3) for BrCa. The median number of prior lines of systemic therapy was 2 in the SCLC cohort, 2 in NSCLC, and 6 in BrCa. Prior taxane therapy was received by 7% of patients in the SCLC cohort, 36% in NSCLC, and 64% in BrCa. The most common adverse events (AEs) in SCLC were fatigue, increased aspartate aminotransferase, diarrhea, and headache (21%, n=3 for each AE); fatigue was the most common AE in NSCLC (58%, n=21; Grade 3/4: 3%, n=1) and in BrCa (61%, n=17). Thrombocytopenia, a result of the systemic effects of BCL-XL inhibitors, was not observed in the Mirzo-C monotherapy cohort. Neutropenia/decreased neutrophil count was not observed in the SCLC monotherapy cohort but was common with BrCa paclitaxel combo (64%, n=18; Grade 3/4: 29%, n=8) and NSCLC docetaxel combo (53%, n=19; Grade 3/4: 44%, n=16); 5 patients in the NSCLC cohort (14%) and 1 in BrCa (4%) had febrile neutropenia. Confirmed ORR was 0% in the SCLC cohort, 11% in NSCLC, and 18% in BrCa. Conclusions: Mirzo-C demonstrated a tolerable safety profile as monotherapy and with taxanes. No thrombocytopenia or neutropenia was observed with monotherapy. No single-agent activity of Mirzo-C was observed in SCLC. Combination treatments were active with high best overall response (BOR) and disease control rates in heavily pretreated NSCLC and BrCa patients, where Grade 3/4 neutropenia was observed. It is unknown if Mirzo-C exacerbated the neutropenia risk associated with taxanes. Clinical trial information: NCT03595059 . [Table: see text]

Immunotherapy combined with rh-endostatin improved clinical outcomes over ICIs plus chemotherapy for second-line treatment of advanced NSCLC.

e21133 Background: Despite the fact that numerous clinical and preclinical studies have demonstrated the synergistic effects of combining antiangiogenic or chemotherapy with immunotherapy, no data have been found to indicate that combination therapy is more effective and safer as second-line therapy. Methods: We retrospectively compared the effectiveness and safety of ICIs plus rh-endostatin to ICIs plus chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). The evaluation indicators were progression-free survival (PFS), safety profile, overall response rate (ORR), disease control rate (DCR) and 1-year survival rate. Results: The median PFS with immunotherapy plus rh-endostatin (IE) was 7.10 months (95% CI, 4.64 to 9.56) versus 5.13 months (95% CI, 4.29 to 5.97) with immunotherapy plus chemotherapy (IC) (HR, 0.56; 95%CI, 0.33 to 0.95). Treatment-related adverse events of grade 3 or 4 occurred in 7.5% of the IE group versus 25.0% of the IC group. The ORR in the IE group was 35.0% versus 20.8% in the IC group ( P = 0.137), and the DCR in the IE group was 92.5% versus 77.1% in the IC group ( P = 0.049). The 1-year survival rate for the IE group was 69.4%, which was higher than the IC group's rate of 61.4%. Conclusions: Our study demonstrates that ICIs in conjunction with endostatin therapy, demonstrate high efficacy and safety, suggesting that such a combination of therapy may be a viable treatment option for pretreated NSCLC patients in the future.

Abstract 5506: Circulating immature neutrophils early detect hyperprogressive disease upon first-line PD-1/PD-L1 inhibitors in non-small cell lung cancer patients selecting best candidates for platinum-based chemotherapy and PD-1/PD-L1 inhibitors combinations

Abstract Background: Hyperprogressive disease (HPD) has been described in ≃14-25% of pretreated non-small cell lung cancer (NSCLC) patients upon single-agent (SA) PD-1/PD-L1 inhibitors (ICI) and has not been reported upon platinum-based chemotherapy (PCT) and ICI combinations. So far, no predictive biomarkers are available for HPD early detection. Methods: NSCLC patients treated with 1st line SA-ICI or PCT-ICI were assessed for HPD and circulating neutrophils. HPD was defined as delta tumor growth rate (TGR) &amp;gt;50% and/or TGR ratio ≥2. Circulating low density neutrophils (LDNs) were assessed by flow cytometry on peripheral blood mononuclear cells (PMBCs). LDNs were defined as CD66b+CD15+ cells among CD11b+ PBMCs and immature subtypes as CD10− LDNs. The LDNs predictive role was assessed by penalized model-based tests. Results: 144 NSCLC patients were included: 75 treated with SA-ICI, 69 with PCT-ICI. In the SA-ICI cohort, HPD occurred in 8 (11%) patients, while progressive disease (PD) and response or stable disease (PR/SD) occurred in 33 (44%) and 34 (45%) of patients respectively. Immature circulating CD10− LDNs were significantly higher in baseline blood samples of HPD patients [median (ME): 39.3, interquartile range (IQR): 28.7] compared to PD [ME: 7.4, IQR: 14.9, p&amp;lt;0.01] or PR/SD patients [ME: 3.7, IQR: 12.6, p&amp;lt;0.01]. Circulating CD10− LDNs were associated with HPD [odds ratio (OR): 1.17, 95% CI: 1.06; 1.29], with a good prediction capability [cross-validated AUC 0.97 (95%CI: 0.94;1.00)]. A 30.5% cut-off value for CD10− LDNs circulating neutrophils was identified by Younden index to discriminate HPD from others. In the PCT-ICI cohort, 14 patients had circulating CD10− LDNs ≥30.5%, being at high risk of HPD. However, no HPD was observed in PCT-ICI cohort and dynamic LDNs evaluation in high HPD risk patients showed 52.3% (IQR: 28.4) median reduction in CD10− LDNs upon PCT-ICI, versus only 8.9% (IQR: 34.6) reduction in HPD patients upon SA-ICI, suggesting that PCT prevents HPD by reducing selectively immature LDNs. Conclusions: Baseline circulating immature neutrophils characterize HPD upon 1st line SA-ICI and a 30.5% cut-off of immature neutrophils could select NSCLC patients to be addressed to PCT-ICI combinations. Citation Format: Roberto Ferrara, Giuseppe Lo Russo, Chiara Maura Ciniselli, Annamaria Piva, Barbara Bassani, Elena Jachetti, Giuseppina Calareso, Valeria Duroni, Settimio Di Gregorio, Claudia Proto, Arsela Prelaj, Alessandro De Toma, Mario Occhipinti, Marta Brambilla, Sara Manglaviti, Laura Mazzeo, Arturo Rinaldi, Teresa Beninato, Monica Ganzinelli, Filippo De Braud, Marina Chiara Garassino, Paolo Verderio, Mario Paolo Colombo, Sabina Sangaletti. Circulating immature neutrophils early detect hyperprogressive disease upon first-line PD-1/PD-L1 inhibitors in non-small cell lung cancer patients selecting best candidates for platinum-based chemotherapy and PD-1/PD-L1 inhibitors combinations. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5506.

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.

Targeted therapies for KRAS-mutant non-small cell lung cancer: from preclinical studies to clinical development-a narrative review.

Non-small cell lung cancer (NSCLC) with Kirsten rat sarcoma viral oncogene homolog (KRAS) driver alterations harbors a poor prognosis with standard therapies, including chemotherapy and/or immunotherapy with anti-programmed cell death protein 1 (anti-PD-1) or anti-programmed death ligand-1 (anti-PD-L1) antibodies. Selective KRAS G12C inhibitors have been shown to provide significant clinical benefit in pretreated NSCLC patients with KRAS G12C mutation. In this review, we describe KRAS and the biology of KRAS-mutant tumors and review data from preclinical studies and clinical trials on KRAS-targeted therapies in NSCLC patients with KRAS G12C mutation. KRAS is the most frequently mutated oncogene in human cancer. The G12C is the most common KRAS mutation found in NSCLC. Sotorasib is the first, selective KRAS G12C inhibitor to receive approval based on demonstration of significant clinical benefit and tolerable safety profile in previously treated, KRAS G12C-mutated NSCLC. Adagrasib, a highly selective covalent inhibitor of KRAS G12C, has also shown efficacy in pretreated patients and other novel KRAS inhibitors are being under evaluation in early-phase studies. Similarly to other oncogene-directed therapies, mechanisms of intrinsic and acquired resistance limiting the activity of these agents have been described. The discovery of selective KRAS G12C inhibitors has changed the therapeutic scenario of KRAS G12C-mutant NSCLC. Various studies testing KRAS inhibitors in different settings of disease, as single-agent or in combination with targeted agents for synthetic lethality and immunotherapy, are currently ongoing in this molecularly-defined subgroup of patients to further improve clinical outcomes.

Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGF-β and PD-L1, in Patients With Non-Small Cell Lung Cancer Resistant or Refractory to Immune Checkpoint Inhibitors.

Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of transforming growth factor beta receptor II (a TGF-β "trap") fused to a human immunoglobulin G1 monoclonal antibody blocking programmed cell death 1 ligand 1 (PD-L1). We report the efficacy and safety in patients with non-small cell lung cancer (NSCLC) that progressed following anti-PD-(L)1 therapy. In this expansion cohort of NCT02517398-a global, open-label, phase I trial-adults with advanced NSCLC that progressed following chemotherapy and was primary refractory or had acquired resistance to anti-PD-(L)1 treatment received intravenous bintrafusp alfa 1200 mg every 2 weeks until confirmed progression, unacceptable toxicity, or trial withdrawal. The primary endpoint was best overall response (by Response Evaluation Criteria in Solid Tumors version 1.1 adjudicated by independent review committee); secondary endpoints included safety. Eighty-three eligible patients (62 [74.7%] treated with ≥3 prior therapies) received bintrafusp alfa. Four patients (3 primary refractory, 1 acquired resistant) had confirmed partial responses (objective response rate, 4.8%; 95% CI, 1.3%-11.9%), and 9 had stable disease. Tumor cell PD-L1 expression was not associated with response. Nineteen patients (22.9%) experienced grade ≥3 treatment-related adverse events, most commonly asthenia (3 [3.6%]) and fatigue, eczema, and pruritus (2 each [2.4%]). One patient had grade 4 amylase increased. One patient died during treatment for pneumonia before initiation of bintrafusp alfa. Although the primary endpoint was not met, bintrafusp alfa showed some clinical activity and a manageable safety profile in patients with heavily pretreated NSCLC, including prior anti-PD-(L)1 therapy. Tumor responses occurred irrespective of whether disease was primary refractory or had acquired resistance to prior anti-PD-(L)1 therapy.