Association between immune-related adverse events and atezolizumab in previously treated patients with unresectable advanced or recurrent non-small cell lung cancer.

PURPOSE: Real-world, large-scale studies on the association between immune-related adverse events (irAEs) and immune checkpoint inhibitor (ICI) therapy effectiveness are limited. We evaluated overall survival (OS) and progression-free survival based on the occurrence and grade of irAEs. PATIENTS AND METHODS: We used data from Japanese patients with unresectable advanced or recurrent non-small cell lung cancer (NSCLC) who received atezolizumab and were enrolled in J-TAIL, a multicenter, prospective, single-arm observational study. RESULTS: Among the 1,002 patients, 190 (19.0%) developed irAEs. The most common irAEs were skin disorders (3.8%) of any grade and interstitial lung disease (1.5%) of grade ≥3. Patients who developed irAEs within 4 or 6 weeks of treatment initiation had higher baseline C-reactive protein levels than those without irAEs. OS was longer in patients with irAEs (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.54-0.82), particularly in those with low-grade irAEs (HR, 0.45; 95% CI, 0.33-0.62), than in patients without irAEs. The HR (95% CI) for OS in patients with low-grade and high-grade skin or endocrine disorder-related irAEs was 0.42 (0.28-0.64) and 0.37 (0.15-0.88), respectively. The HR (95% CI) for OS in patients with low-grade and high-grade irAEs other than skin or endocrine disorders was 0.44 (0.30-0.65) and 1.27 (0.96-1.69), respectively. CONCLUSIONS: In patients with unresectable advanced or recurrent NSCLC treated with atezolizumab in real-world settings, irAEs are associated with a clinical benefit except in those with high-grade irAEs other than skin and endocrine disorders.

A Phase I First-in-Human Study of ABBV-011, a Seizure-Related Homolog Protein 6-Targeting Antibody-Drug Conjugate, in Patients With Small Cell Lung Cancer.

PURPOSE: Seizure-related homolog protein 6 (SEZ6) is a novel target expressed in small cell lung cancer (SCLC). ABBV-011, a SEZ6-targeted antibody conjugated to calicheamicin, was evaluated in a phase I study (NCT03639194) in patients with relapsed/refractory SCLC. We report initial outcomes of ABBV-011 monotherapy. PATIENTS AND METHODS: ABBV-011 was administered intravenously once every 3 weeks (Q3W) during dose escalation (0.3-2 mg/kg) and expansion. Patients with SEZ6-positive tumors (≥25% of tumor cells with ≥1+ staining intensity by immunohistochemistry) were preselected for expansion. Safety, tolerability, antitumor activity, and pharmacokinetics were evaluated. RESULTS: As of August 2022, 99 patients received ABBV-011 monotherapy (dose escalation, n=36; Japanese dose evaluation, n=3; dose expansion, n=60 [1 mg/kg, n=40]); median age was 63 years (range, 41-79). Thirty-two percent, 41%, and 26% of patients received 1, 2, and ≥3 prior therapies, respectively. The maximum tolerated dose was not reached through 2.0 mg/kg. Most common treatment-emergent adverse events (TEAEs) were fatigue (50%), nausea (42%), and thrombocytopenia (41%). Most common hepatic TEAEs were increased aspartate aminotransferase (22%), increased g-glutamyltransferase (21%), and hyperbilirubinemia (17%); 2 patients experienced veno-occlusive liver disease. Objective response rate (ORR) was 19% (19/98). In the 1-mg/kg dose-expansion cohort (n=40), ORR was 25%; median response duration was 4.2 months (95% CI, 2.6-6.7) and median progression-free survival was 3.5 months (95% CI, 1.5-4.2). CONCLUSIONS: ABBV-011 1.0 mg/kg Q3W monotherapy was well tolerated and demonstrated encouraging antitumor activity in heavily pretreated patients with relapsed/refractory SCLC. SEZ6 is a promising novel SCLC target and warrants further investigation.

Unsuccessful rechallenge with nivolumab in a patient with advanced non-small cell lung cancer who had a 6-year complete response and treatment-free period: Case report.

Several predictive factors of immune checkpoint inhibitor response have been reported, but there has not been sufficient exploration of which patients benefit from immune checkpoint inhibitor rechallenge. We report the case of a patient with non-small cell lung cancer who had 6 years of complete response with initial nivolumab treatment. After relapse, however, rechallenge with nivolumab did not result in tumour shrinkage or long-term response. Even in patients who had an exceptional response to the initial immune checkpoint inhibitor, long-term efficacy may not be achieved by immune checkpoint inhibitor rechallenge. Thorough investigation of biomarkers that predict efficacy of immune checkpoint inhibitor rechallenge is warranted.

Comparison of platinum combination chemotherapy plus pembrolizumab versus platinum combination chemotherapy plus nivolumab-ipilimumab for treatment-naive advanced non-small-cell lung cancer in Japan (JCOG2007): an open-label, multicentre, randomised, phase 3 trial.

BACKGROUND: The combination of platinum-based chemotherapy and an antibody to PD-1 or to its ligand PD-L1, with or without an antibody to CTLA-4, has improved the survival of individuals with metastatic non-small-cell lung cancer (NSCLC). However, no randomised controlled trial has evaluated the survival benefit of adding a CTLA-4 inhibitor to platinum-based chemotherapy plus a PD-1 or PD-L1 inhibitor. METHODS: This open-label, randomised, phase 3 trial was conducted at 48 hospitals in Japan. Eligible patients were aged 20 years or older with previously untreated advanced NSCLC and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with known driver oncogenes were excluded. Participants were randomly assigned (1:1) to receive platinum-based chemotherapy (four cycles) plus pembrolizumab (pembrolizumab group) or platinum-based chemotherapy (two cycles) plus nivolumab-ipilimumab (nivolumab-ipilimumab group). The primary endpoint was overall survival and assessed in all randomly assigned patients on an intention-to-treat basis. The trial is registered in the Japan Registry for Clinical Trials, jRCTs031210013, and is now closed to new enrolment and is ongoing. FINDINGS: Between patient accrual initiation on April 6, 2021, and discontinuation of the trial on March 30, 2023, 11 (7%) of 148 patients in the nivolumab-ipilimumab group had a treatment-related death. Because of the high number of treatment-related deaths, patient accrual was terminated early, resulting in 295 patients (236 [80%] male and 59 [20%] female) enrolled; the primary analysis was done on the basis of 117 deaths (fewer than the required 329 deaths). By May 25, 2023 (data cutoff), overall survival did not differ significantly between the nivolumab-ipilimumab group and the pembrolizumab group (median 23·7 months [95% CI 17·6-not estimable] vs 20·5 months [17·6-not estimable], respectively; hazard ratio 0·98 [90% CI 0·72-1·34]; p=0·46). Non-haematological adverse events of grade 3 or worse occurred in 87 (60%) of 146 patients in the nivolumab-ipilimumab group and 59 (41%) of 144 patients in the pembrolizumab group. The pembrolizumab group tended to have a better quality of life compared with the nivolumab-ipilimumab group. INTERPRETATION: The safety and efficacy data suggest an unfavourable benefit-risk profile for nivolumab-ipilimumab combined with platinum-based chemotherapy relative to pembrolizumab combined with platinum-based chemotherapy as a first-line treatment for patients with advanced NSCLC, although a definitive conclusion awaits an updated analysis of overall survival. FUNDING: The National Cancer Center Research and Development Fund and Japan Agency for Medical Research and Development.

Real-World Pharmacokinetics, Effectiveness, and Safety of Atezolizumab in Patients With Unresectable Advanced or Recurrent NSCLC: An Exploratory Study of J-TAIL.

Introduction: This study validated real-world pharmacokinetic (PK) data using an established population PK (PopPK) model for atezolizumab in Japanese patients with NSCLC and explored the relationship between PK parameters, effectiveness, and adverse events (AEs) for the 1200 mg once every three weeks regimen. Methods: A subgroup of 262 of 1039 patients from J-TAIL consented to this exploratory research for PK evaluation of atezolizumab monotherapy for unresectable advanced/recurrent NSCLC (August 2018 to October 2019; 197 institutions). We evaluated plasma concentrations before the start of the third cycle of atezolizumab infusion classified into quartiles 1 to 4, their association with effectiveness, and the association between atezolizumab maximum plasma concentrations (Cmax) calculated using the existing PopPK model and AEs of special interest (AESIs). Results: Overall, 175 of 262 patients were included; baseline characteristics were similar to those of patients enrolled in J-TAIL (Eastern Cooperative Oncology Group performance status ≥ 2, 12.0%; age ≥ 75 y, 28.9%; atezolizumab as more than or equal to third-line treatment, 57.5%). Atezolizumab plasma concentrations were similar to previously reported data among Japanese/non-Japanese patients. The overall survival was significantly shorter in patients with lower atezolizumab plasma concentrations in Q1 versus Q2 to Q4, although progression-free survival remained the same. The PK data adequately fit the PopPK model, with the frequency of AESIs increasing as the calculated Cmax at cycle 1 increased. Conclusions: In real-world Japanese patients with unresectable advanced/recurrent NSCLC, PKs were similar to previous reports. Certain patient populations had shorter overall survival, and atezolizumab plasma concentrations in cycle 3 were lower in this population. Elevated Cmax at cycle 1 may be associated with an increased frequency of AESIs.

Can FDG-PET after neoadjuvant chemotherapy plus nivolumab predict residual disease in non-small cell lung cancer?

Neoadjuvant therapy with nivolumab improves event-free survival (EFS) in patients with resectable non-small cell lung cancer, and a pathological complete response is a predictor of longer EFS. We assessed metabolic responses using 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) before and after neoadjuvant treatment to explore its surrogacy for pathological complete response (pCR). We describe three patients with squamous cell lung carcinoma who underwent neoadjuvant therapy with nivolumab plus chemotherapy, followed by surgery. In Cases 1 and 2, preoperative tumour response were PR per RECIST and demonstrated marked metabolic response on FDG-PET after neoadjuvant therapy, with both resected tumours showing a pCR. On the other hand, Case 3 showed a tumour response before surgery (PR per RECIST), however, the tumour, maintained FDG uptake (19.5 → 15.1), and the resected tumour remained residual cells (RVT, 15%). Thus, reduction of FDG uptake on FDG-PET can predict the pathological response to neoadjuvant therapy with nivolumab.

Subcutaneous Versus Intravenous Amivantamab, Both in Combination With Lazertinib, in Refractory Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer: Primary Results From the Phase III PALOMA-3 Study.

PURPOSE: Phase III studies of intravenous amivantamab demonstrated efficacy across epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). A subcutaneous formulation could improve tolerability and reduce administration time while maintaining efficacy. PATIENTS AND METHODS: Patients with EGFR-mutated advanced NSCLC who progressed after osimertinib and platinum-based chemotherapy were randomly assigned 1:1 to receive subcutaneous or intravenous amivantamab, both combined with lazertinib. Coprimary pharmacokinetic noninferiority end points were trough concentrations (Ctrough; on cycle-2-day-1 or cycle-4-day-1) and cycle-2 area under the curve (AUCD1-D15). Key secondary end points were objective response rate (ORR) and progression-free survival (PFS). Overall survival (OS) was a predefined exploratory end point. RESULTS: Overall, 418 patients underwent random assignment (subcutaneous group, n = 206; intravenous group, n = 212). Geometric mean ratios of Ctrough for subcutaneous to intravenous amivantamab were 1.15 (90% CI, 1.04 to 1.26) at cycle-2-day-1 and 1.42 (90% CI, 1.27 to 1.61) at cycle-4-day-1; the cycle-2 AUCD1-D15 was 1.03 (90% CI, 0.98 to 1.09). ORR was 30% in the subcutaneous and 33% in the intravenous group; median PFS was 6.1 and 4.3 months, respectively. OS was significantly longer in the subcutaneous versus intravenous group (hazard ratio for death, 0.62; 95% CI, 0.42 to 0.92; nominal P = .02). Fewer patients in the subcutaneous group experienced infusion-related reactions (IRRs; 13% v 66%) and venous thromboembolism (9% v 14%) versus the intravenous group. Median administration time for the first infusion was reduced to 4.8 minutes (range, 0-18) for subcutaneous amivantamab and to 5 hours (range, 0.2-9.9) for intravenous amivantamab. During cycle-1-day-1, 85% and 52% of patients in the subcutaneous and intravenous groups, respectively, considered treatment convenient; the end-of-treatment rates were 85% and 35%, respectively. CONCLUSION: Subcutaneous amivantamab-lazertinib demonstrated noninferiority to intravenous amivantamab-lazertinib, offering a consistent safety profile with reduced IRRs, increased convenience, and prolonged survival.

Neoadjuvant nivolumab plus chemotherapy followed by resection for superior sulcus tumour with high PD-L1 expression: A case report.

The standard treatment for resectable non-small cell lung cancer (NSCLC) located in the superior sulcus is neoadjuvant chemoradiotherapy followed by highly invasive resection. Based on the results of the CheckMate 816 trial, which showed a marked improvement in the efficacy of neoadjuvant chemo-immunotherapy, we report a case of minimally invasive resection after neoadjuvant nivolumab plus chemotherapy for superior sulcus NSCLC, resulting in a pathologic complete response. The patient was a 76-year-old man with a 65-mm right superior sulcus tumour diagnosed as squamous cell carcinoma with 95% PD-L1. After two courses of neoadjuvant nivolumab plus chemotherapy, the tumour was completely resected through an 11-cm right lateral thoracotomy with second rib resection and first rib preservation. No residual tumour cells were observed in the specimen, and the patient had a pathologic complete response. This report represents a new treatment option for superior sulcus tumours.

Mannitol versus furosemide in patients with thoracic malignancies who received cisplatin-based chemotherapy using short hydration: A randomized phase II trial.

BACKGROUND: Mannitol is exclusively recommended in the National Comprehensive Cancer Network guidelines for diuresis in cisplatin (CDDP)-based chemotherapy. The utility of furosemide, a widely used and convenient diuretic, thus requires clarification. METHODS: This is a prospective, single-centered, open-label, noninferiority phase II study. Patients with thoracic malignancies who planned to receive CDDP-based chemotherapy were randomly assigned to receive either mannitol (arm A) or furosemide (arm B). The primary end point was set as the proportion of patients who experienced any grade of "creatinine (Cr) increased" based on the upper limit of the normal range (ULN) during the first cycle as assessed by Common Terminology Criteria for Adverse Events Version 4.0. Secondary end points were Cr increased based on the baseline value during the first cycle, Cr increased after the completion of CDDP, and the proportion of patients with phlebitis. RESULTS: Between April 2018 and March 2022, 115 patients were enrolled and 106 were analyzed. Any grade of Cr increased based on the ULN during the first cycle was 17.3% (arm A) and 24.1% (arm B), respectively (p = 0.34). Therefore, the primary end point was not met. After completion of chemotherapy, any grade of Cr increased was observed in 23.1% (arm A) and 31.5% (arm B), respectively. However, the actual serum Cr level and Cr clearance during the courses were not different between the arms. Phlebitis occurred more frequently in arm A (28.8%) than arm B (16.7%). CONCLUSIONS: Mannitol should remain the standard diuresis in CDDP-based chemotherapy assessed by conventional CTCAE grading, but furosemide can be room for consideration when assessed by actual serum Cr level and Cr clearance.

PRMT5 is an actionable therapeutic target in CDK4/6 inhibitor-resistant ER+/RB-deficient breast cancer.

CDK4/6 inhibitors (CDK4/6i) have improved survival of patients with estrogen receptor-positive (ER+) breast cancer. However, patients treated with CDK4/6i eventually develop drug resistance and progress. RB1 loss-of-function alterations confer resistance to CDK4/6i, but the optimal therapy for these patients is unclear. Through a genome-wide CRISPR screen, we identify protein arginine methyltransferase 5 (PRMT5) as a molecular vulnerability in ER+/RB1-knockout breast cancer cells. Inhibition of PRMT5 blocks the G1-to-S transition in the cell cycle independent of RB, leading to growth arrest in RB1-knockout cells. Proteomics analysis uncovers fused in sarcoma (FUS) as a downstream effector of PRMT5. Inhibition of PRMT5 results in dissociation of FUS from RNA polymerase II, leading to hyperphosphorylation of serine 2 in RNA polymerase II, intron retention, and subsequent downregulation of proteins involved in DNA synthesis. Furthermore, treatment with the PRMT5 inhibitor pemrametostat and a selective ER degrader fulvestrant synergistically inhibits growth of ER+/RB-deficient cell-derived and patient-derived xenografts. These findings highlight dual ER and PRMT5 blockade as a potential therapeutic strategy to overcome resistance to CDK4/6i in ER+/RB-deficient breast cancer.

Machine learning analysis of pathological images to predict 1-year progression-free survival of immunotherapy in patients with small-cell lung cancer.

BACKGROUND: In small-cell lung cancer (SCLC), the tumor immune microenvironment (TIME) could be a promising biomarker for immunotherapy, but objectively evaluating TIME remains challenging. Hence, we aimed to develop a predictive biomarker of immunotherapy efficacy through a machine learning analysis of the TIME. METHODS: We conducted a biomarker analysis in a prospective study of patients with extensive-stage SCLC who received chemoimmunotherapy as the first-line treatment. We trained a model to predict 1-year progression-free survival (PFS) using pathological images (H&E, programmed cell death-ligand 1 (PD-L1), and double immunohistochemical assay (cluster of differentiation 8 (CD8) and forkhead box P3 (FoxP3)) and patient information. The primary outcome was the mean area under the curve (AUC) of machine learning models in predicting the 1-year PFS. RESULTS: We analyzed 100,544 patches of pathological images from 78 patients. The mean AUC values of patient information, pathological image, and combined models were 0.789 (range 0.571-0.982), 0.782 (range 0.750-0.911), and 0.868 (range 0.786-0.929), respectively. The PFS was longer in the high efficacy group than in the low efficacy group in all three models (patient information model, HR 0.468, 95% CI 0.287 to 0.762; pathological image model, HR 0.334, 95% CI 0.117 to 0.628; combined model, HR 0.353, 95% CI 0.195 to 0.637). The machine learning analysis of the TIME had better accuracy than the human count evaluations (AUC of human count, CD8-positive lymphocyte: 0.681, FoxP3-positive lymphocytes: 0.626, PD-L1 score: 0.567). CONCLUSIONS: The spatial analysis of the TIME using machine learning predicted the immunotherapy efficacy in patients with SCLC, thus supporting its role as an immunotherapy biomarker.

NOTCH1 and CREBBP co-mutations negatively affect the benefit of adjuvant therapy in completely resected EGFR-mutated NSCLC: translational research of phase III IMPACT study.

The phase III IMPACT study (UMIN000044738) compared adjuvant gefitinib with cisplatin plus vinorelbine (cis/vin) in completely resected epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Although the primary endpoint of disease-free survival (DFS) was not met, we searched for molecular predictors of adjuvant gefitinib efficacy. Of 234 patients enrolled in the IMPACT study, 202 patients were analyzed for 409 cancer-related gene mutations and tumor mutation burden using resected lung cancer specimens. Frequent somatic mutations included tumor protein p53 (TP53; 58.4%), CUB and Sushi multiple domains 3 (CSMD3; 11.8%), and NOTCH1 (9.9%). Multivariate analysis showed that NOTCH1 co-mutation was a significant poor prognostic factor for overall survival (OS) in the gefitinib group and cAMP response element binding protein (CREBBP) co-mutation for DFS and OS in the cis/vin group. In patients with NOTCH1 co-mutations, gefitinib group had a shorter OS than cis/vin group (Hazard ratio 5.49, 95% CI 1.07-28.00), with a significant interaction (P for interaction = 0.039). In patients with CREBBP co-mutations, the gefitinib group had a longer DFS than the cis/vin group, with a significant interaction (P for interaction = 0.058). In completely resected EGFR-mutated NSCLC, NOTCH1 and CREBBP mutations might predict poor outcome in patients treated with gefitinib and cis/vin, respectively.

A Phase II Study of High-Flow Nasal Cannula for Relieving Dyspnea in Advanced Cancer Patients.

CONTEXT: The efficacy and tolerability of high-flow nasal cannula (HFNC) for relieving dyspnea in advanced cancer patients with limited prognosis requires elucidation. OBJECTIVES: The primary aim of this trial was to assess the efficacy and tolerability of HFNC regarding dyspnea including severe as well as moderate for longer durations in patients under palliative care. METHODS: In this prospective study, hospitalized patients with advanced cancer who had dyspnea at rest (numeric rating scale, NRS≥3) and hypoxemia were enrolled. They were treated with HFNC for five days in the respiratory unit. Primary endpoint was mean change of modified Borg scale at 24 hours. Key secondary endpoints consisted of mean changes in modified Borg scale during the study period and feasibility (Trial Identifier, UMIN000035738). RESULTS: Between February 2019 and February 2022, 25 patients were enrolled and 21 were analyzed. Twenty patients used inspired oxygen and the mean fraction of inspired oxygen (FiO2) was 0.34 (range, 0.21-1.0). At baseline, mean NRS (dyspnea) was 5.9 (range, 3-10). Median survival time was 19 days (range, 3-657). The mean change of modified Borg scale was 1.4 (80% confidence interval [CI]: 0.8-1.9) at 24 hours, 12 patients (57%) showed 1.0 points improvement of modified Borg scale. Within two hours, 15 patients showed 1.0 points improvement of modified Borg scale and such early responders were likely to maintain dyspnea improvement for 24 hours. Nineteen patients could continue HFNC for 24 hours and 11 patients completed five days of HFNC. CONCLUSION: To our knowledge, this trial is the first prospective study to assess the five-day efficacy and tolerability of HFNC for dyspnea in patients under palliative care. Although this did not reach the prespecified endpoint, about half of the patients showed 1.0 point improvement, a minimally clinically important difference (MCID) in the chronic lung disease. HFNC can be a palliative treatment option in advanced cancer patients with dyspnea.

Adjacent angle size correlates with diagnostic sensitivity of endobronchial ultrasonography with a guide sheath.

Background: An association exists among the diagnostic yield of transbronchial biopsy using endobronchial ultrasonography with a guide sheath (EBUS-GS-TBB) and several factors, such as simple within or adjacent endobronchial ultrasonography (EBUS) findings. Here, we aimed to investigate whether more detailed EBUS findings affect the diagnostic yield of lung cancer in EBUS-GS-TBB. Methods: We conducted this retrospective single-center cohort study, enrolling consecutive patients with lung cancer who underwent EBUS-GS-TBB. The primary outcome was examination of predictive factors affecting the diagnostic yield of lung cancer using EBUS-GS-TBB. The secondary outcome was a subgroup analysis of within and adjacent lesions. The adjacent angle was defined as the angle formed by the midpoint of the probe and the two points where the edge of the probe and shadow of the tumor intersected. Results: Of the 179 lesions investigated, 140 (78.2%) were diagnosed using EBUS-GS-TBB. The diagnostic yields of within and adjacent lesions were 91.6% and 51.7%, respectively. In the multivariable analysis, within lesions had significantly higher diagnostic yields than did the adjacent lesions (P<0.001). The adjacent angle was larger in lesions diagnosed using EBUS-GS-TBB than in undiagnosed lesions (P=0.003). In adjacent lesions, the diagnostic yields were 75.0% and 36.1% for lesions ≥180° and <180°, respectively. Conclusions: In adjacent lesions, the diagnostic yields differed significantly depending on the adjacent angle. Even if EBUS findings are adjacent, the operator should identify the branch of the bronchus with a greater adjacent angle. Future studies should investigate improvements in diagnostic yields via additional procedures for lesions with small adjacent angles.

Biomarker Testing in Patients With Unresectable Advanced or Recurrent Non-Small Cell Lung Cancer.

Importance: Biomarker testing for driver mutations is essential for selecting appropriate non-small cell lung cancer (NSCLC) treatment but is insufficient. Objective: To investigate the status of biomarker testing and drug therapy for NSCLC in Japan for identifying problems in treatment. Design, Setting, and Participants: The REVEAL cohort study included retrospective data collection and prospective follow-up from 29 institutions across Japan. Of 1500 patients diagnosed with advanced or recurrent NSCLC between January 1 and March 18, 2021, 1479 were eligible. Cases recognized at the wrong clinical stage (n = 12), diagnosed outside the study period (n = 6), not treated according to eligibility criteria before recurrence (n = 2), and with deficient consent acquisition procedure (n = 1) were excluded. Main Outcomes and Measures: The primary end point was the biomarker testing status. Treatment-related factors were examined. Results: Among the 1479 patients included in the analysis, the median age was 72 (range, 30-95) years; 1013 (68.5%) were men; 1161 (78.5%) had an Eastern Cooperative Oncology Group performance status 0 or 1; 1097 (74.2%) were current or past smokers; and 947 (64.0%) had adenocarcinoma. Biomarker status was confirmed in 1273 patients (86.1%). Multigene testing was performed in 705 cases (47.7%); single-gene testing, in 847 (57.3%); and both, in 279 (18.9%). Biomarker testing was performed for EGFR in 1245 cases (84.2%); ALK, in 1165 (78.8%); ROS1, in 1077 (72.8%); BRAF, in 803 (54.3%); and MET, in 805 (54.4%). Positivity rates among 898 adenocarcinoma cases included 305 (34.0%) for EGFR, 29 (3.2%) for ALK, 19 (2.1%) for ROS1, 11 (1.2%) for BRAF, and 14 (1.6%) for MET. Positivity rates among 375 nonadenocarcinoma cases were 14 (3.7%) for EGFR, 6 (1.6%) for ALK, 1 (0.3%) for ROS1, 3 (0.8%) for BRAF, and 8 (2.1%) for MET. Poor physical status, squamous cell carcinoma, and other comorbidities were associated with hampered multigene testing. Targeted therapy was received as first-line treatment by 263 of 278 cases (94.6%) positive for EGFR, 25 of 32 (78.1%) positive for ALK, 15 of 24 (62.5%) positive for ROS1, 9 of 12 (75.0%) positive for BRAF, and 12 of 19 (63.2%) positive for MET. Median overall survival of patients with positive findings for driver gene alteration and who received targeted therapy was 24.3 (95% CI, not reported) months; with positive findings for driver gene alteration and who did not receive targeted therapy, 15.2 (95% CI, 7.7 to not reported) months; and with negative findings for driver gene alteration, 11.0 (95% CI, 10.0-12.5) months. Multigene testing for nonadenocarcinomas and adenocarcinomas accounted for 705 (47.7%) of all NSCLC cases. Conclusions and Relevance: These findings suggest that multigene testing has not been sufficiently implemented in Japan and should be considered prospectively, even in nonadenocarcinomas, to avoid missing rare driver gene alterations.

Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer.

BACKGROUND: Neoadjuvant or adjuvant immunotherapy can improve outcomes in patients with resectable non-small-cell lung cancer (NSCLC). Perioperative regimens may combine benefits of both to improve long-term outcomes. METHODS: We randomly assigned patients with resectable NSCLC (stage II to IIIB [N2 node stage] according to the eighth edition of the AJCC Cancer Staging Manual) to receive platinum-based chemotherapy plus durvalumab or placebo administered intravenously every 3 weeks for 4 cycles before surgery, followed by adjuvant durvalumab or placebo intravenously every 4 weeks for 12 cycles. Randomization was stratified according to disease stage (II or III) and programmed death ligand 1 (PD-L1) expression (≥1% or <1%). Primary end points were event-free survival (defined as the time to the earliest occurrence of progressive disease that precluded surgery or prevented completion of surgery, disease recurrence [assessed in a blinded fashion by independent central review], or death from any cause) and pathological complete response (evaluated centrally). RESULTS: A total of 802 patients were randomly assigned to receive durvalumab (400 patients) or placebo (402 patients). The duration of event-free survival was significantly longer with durvalumab than with placebo; the stratified hazard ratio for disease progression, recurrence, or death was 0.68 (95% confidence interval [CI], 0.53 to 0.88; P = 0.004) at the first interim analysis. At the 12-month landmark analysis, event-free survival was observed in 73.4% of the patients who received durvalumab (95% CI, 67.9 to 78.1), as compared with 64.5% of the patients who received placebo (95% CI, 58.8 to 69.6). The incidence of pathological complete response was significantly greater with durvalumab than with placebo (17.2% vs. 4.3% at the final analysis; difference, 13.0 percentage points; 95% CI, 8.7 to 17.6; P<0.001 at interim analysis of data from 402 patients). Event-free survival and pathological complete response benefit were observed regardless of stage and PD-L1 expression. Adverse events of maximum grade 3 or 4 occurred in 42.4% of patients with durvalumab and in 43.2% with placebo. Data from 62 patients with documented EGFR or ALK alterations were excluded from the efficacy analyses in the modified intention-to-treat population. CONCLUSIONS: In patients with resectable NSCLC, perioperative durvalumab plus neoadjuvant chemotherapy was associated with significantly greater event-free survival and pathological complete response than neoadjuvant chemotherapy alone, with a safety profile that was consistent with the individual agents. (Funded by AstraZeneca; AEGEAN ClinicalTrials.gov number, NCT03800134.).

Tarlatamab for Patients with Previously Treated Small-Cell Lung Cancer.

BACKGROUND: Tarlatamab, a bispecific T-cell engager immunotherapy targeting delta-like ligand 3 and CD3, showed promising antitumor activity in a phase 1 trial in patients with previously treated small-cell lung cancer. METHODS: In this phase 2 trial, we evaluated the antitumor activity and safety of tarlatamab, administered intravenously every 2 weeks at a dose of 10 mg or 100 mg, in patients with previously treated small-cell lung cancer. The primary end point was objective response (complete or partial response), as assessed by blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: Overall, 220 patients received tarlatamab; patients had previously received a median of two lines of treatment. Among patients evaluated for antitumor activity and survival, the median follow-up was 10.6 months in the 10-mg group and 10.3 months in the 100-mg group. An objective response occurred in 40% (97.5% confidence interval [CI], 29 to 52) of the patients in the 10-mg group and in 32% (97.5% CI, 21 to 44) of those in the 100-mg group. Among patients with an objective response, the duration of response was at least 6 months in 59% (40 of 68 patients). Objective responses at the time of data cutoff were ongoing in 22 of 40 patients (55%) in the 10-mg group and in 16 of 28 patients (57%) in the 100-mg group. The median progression-free survival was 4.9 months (95% CI, 2.9 to 6.7) in the 10-mg group and 3.9 months (95% CI, 2.6 to 4.4) in the 100-mg group; the estimates of overall survival at 9 months were 68% and 66% of patients, respectively. The most common adverse events were cytokine-release syndrome (in 51% of the patients in the 10-mg group and in 61% of those in the 100-mg group), decreased appetite (in 29% and 44%, respectively), and pyrexia (in 35% and 33%). Cytokine-release syndrome occurred primarily during treatment cycle 1, and events in most of the patients were grade 1 or 2 in severity. Grade 3 cytokine-release syndrome occurred less frequently in the 10-mg group (in 1% of the patients) than in the 100-mg group (in 6%). A low percentage of patients (3%) discontinued tarlatamab because of treatment-related adverse events. CONCLUSIONS: Tarlatamab, administered as a 10-mg dose every 2 weeks, showed antitumor activity with durable objective responses and promising survival outcomes in patients with previously treated small-cell lung cancer. No new safety signals were identified. (Funded by Amgen; DeLLphi-301 ClinicalTrials.gov number, NCT05060016.).

Randomized, open-label phase II study of brigatinib and carboplatin plus pemetrexed and brigatinib alone for chemotherapy-naive patients with ALK-rearranged non-squamous non-small cell lung cancer: treatment rationale and protocol design of the B-DASH study (WJOG 14720 L).

BACKGROUND: The ALTA-1L study compared brigatinib with crizotinib in untreated ALK-rearranged non-small cell lung cancer (NSCLC) patients, demonstrating the efficacy of brigatinib. Although the median progression-free survival (PFS) of brigatinib group was 24.0 months, the one-year PFS rate was 70%. In the NEJ009 study, patients with EGFR mutations showed improved outcomes with gefitinib plus chemotherapy compared with gefitinib monotherapy. To evaluate the efficacy of the combination of brigatinib with chemotherapy for patients with ALK-rearranged NSCLC, we designed B-DASH study (WJOG 14720L). METHODS: B-DASH study is a multicenter, two-arm, phase II study. Eligible patients have untreated stage IIIB, stage IIIC, stage IV, or postoperative relapse ALK-rearranged nonsquamous NSCLC. Patients will be randomized in a 1:1 ratio to receive brigatinib (180 mg once daily with a 7-day lead-in period at 90 mg) monotherapy or carboplatin (area under the curve = 5 on day 1) plus pemetrexed (500 mg/m2 on day 1) and brigatinib in a 3-week cycle for up to four cycles, followed by pemetrexed and brigatinib as maintenance therapy. The target hazard ratio of 0.62 is set based on the NEJ009 study. With one-sided alpha = 0.20 and power = 0.8, the sample size for the B-DASH study was calculated to be 110, considering the possibility of patients dropping out. The primary endpoint is PFS. The key secondary endpoints are the overall response rate and overall survival. We will evaluate tumor-derived DNA from plasma specimens before treatment, 42 days after administering the study drug, and on the day of progressive disease. Recruitment began in November 2021 and is ongoing. DISCUSSION: The efficacy of combination therapy with tyrosine kinase inhibitors and cytotoxic chemotherapy was demonstrated in patients with EGFR mutations but remains unclear in patients with ALK-rearranged NSCLC. The B-DASH study is the only trial of brigatinib combined with chemotherapy in patients with untreated ALK-rearranged NSCLC. TRIAL REGISTRATION: jRCT identifier: jRCTs041210103.

First-line nivolumab, paclitaxel, carboplatin, and bevacizumab for advanced non-squamous non-small cell lung cancer: Updated survival analysis of the ONO-4538-52/TASUKI-52 randomized controlled trial.

BACKGROUND: ONO-4538-52/TASUKI-52 was performed in Japan, Korea, and Taiwan to determine the oncological effectiveness and safety of combining nivolumab or placebo with bevacizumab plus platinum chemotherapy for the initial (first-line) treatment of patients with advanced non-squamous non-small cell lung cancer (nsNSCLC). At the interim analysis (minimum follow-up, 7.4 months), the independent radiology review committee-assessed progression-free survival was significantly longer in the nivolumab arm, but overall survival (OS) data were immature. METHODS: Here, we present the updated OS data. Patients with treatment-naïve stage IIIB/IV or recurrent nsNSCLC without driver mutations in ALK, EGFR, or ROS1, were randomized 1:1 to receive either nivolumab or placebo. Patients in both arms received paclitaxel, carboplatin, and bevacizumab, administered 3-weekly for a maximum of 6 cycles. Nivolumab/placebo and bevacizumab were subsequently continued until disease progression or unacceptable toxicity. RESULTS: Overall, 550 patients were randomized. At the time of the analysis (minimum follow-up: 19.4 months), the median OS was longer in the nivolumab arm than in the placebo arm (30.8 vs. 24.7 months; hazard ratio 0.74, 95% confidence interval 0.58-0.94). The 12-month OS rates were 81.3% vs. 76.3% in the nivolumab vs. placebo arms, respectively. The respective 18-month OS rates were 69.0% vs. 61.9%. CONCLUSION: Nivolumab plus platinum chemotherapy and bevacizumab demonstrated longer OS vs. the placebo combination. We believe this regimen is viable as a standard, first-line treatment for patients with advanced nsNSCLC without driver mutations in ALK, EGFR, or ROS1.