PURPOSE:Clinical outcomes with immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) range from durable disease control to rapid progression. Current biomarkers have limited ability to predict these divergent outcomes. EXPERIMENTAL DESIGN:Spatially-resolved immune subtyping in the TRACERx421 multiregion cohort was used to assess intratumoral immune heterogeneity (ITIH), defined as coexisting immune-enriched and immune-depleted regions. A computational model was used to infer ITIH from single samples, classifying tumors as homogenously immune-enriched (Hom-IE), heterogeneously immune-enriched (Het-IE), heterogeneously immune-depleted (Het-D), and homogenously immune-depleted (Hom-D). ITIH was validated by digital pathology and evaluated in three independent cohorts (n=1,085) of advanced NSCLC patients treated with ICIs. RESULTS:In TRACERx421, ITIH was associated with differences in immune programs among tumors otherwise classified within the same immune subtype. Single-sample ITIH inference recapitulated these patterns, as supported by gradients of tumor-infiltrating lymphocytes detected via digital pathology. Across cohorts, Hom-IE tumors demonstrated longer OS compared to other groups (34.6 vs. 12.1-16.6 months in cohort A; 21.9 vs. 8.4-13.3 months in cohort B; 22.6 vs. 11.3-13.4 months in cohort C). Hom-IE tumors were associated with longer OS regardless of PD-L1 status. Consistently, among PD-L1 low/negative tumors, Hom-IE tumors showed significantly longer OS compared to the non-Hom-IE counterpart. Conversely, the detrimental effects of KEAP1STK11 mutations persisted in the Hom-IE background. CONCLUSIONS:These findings demonstrate that ITIH can be assessed from individual tumor samples, identifies a microenvironment state associated with long-term benefit from immunotherapy, and provides an additional layer of resolution to established and emerging biomarkers.

Supplementary Figure S3. Figure showing overall survival in liquid only group.

Abstract Introduction: Despite major advances with immune checkpoint inhibitors (ICIs) in treatment of metastatic NSCLC, reliable biomarkers to predict who will benefit from therapy and monitor early treatment response remain limited. Thymidine kinase is an enzyme fundamental in the DNA synthesis, its activity reflects tumor cell proliferation and tumor aggressiveness. This study (NCT06823401) is the first to evaluate plasma TKa levels in NSCLC patients receiving immunotherapy (IT) or chemotherapy-IT (CHT-IT). The objectives were to determine whether baseline TKa levels can predict efficacy of IT and if early on-treatment changes in TKa levels reflect treatment response, thereby supporting TKa as a minimally invasive biomarker for patient therapy selection and early efficacy assessment. The capacity of TKa to evaluate cell proliferation is expected to reflect and predict successful T-cell activation of IT and prolonged efficacy. Methods: 94 patients (50 males, 44 females) with metastatic NSCLC, had plasma samples collected at baseline (pre-treatment) and at second treatment cycle of whom 93 received first-line systemic therapy. Circulating TKa was measured using the FDA cleared and CE marked DiviTum® TKa assay (Biovica, Sweden), with values reported in DiviTum units of activity (DuA). Analysis was performed blinded to clinical outcomes. TKa was evaluated for its association with response rate (RR), progression-free survival (PFS), overall survival (OS) and was also correlated to other biomarkers, including PD-L1 expression. Results: 65 pts (70%) received first-line CHT-IT, while 28 pts (30%) received IT alone. PD-L1 expression was <1% in 37 pts (40%), 1-49% in 17 pts (18%), ≥50% in 34 pts (36%), and unknown in 6 pts (6%). The median baseline TKa level was 203 DuA. The RR in the low (<203 DuA) and high-TKa group was 52% and 32% respectively (p = 0.80) while the mPFS was not reached in the low TKa group versus 7.3 mos in high TKa group (p = 0.13). The 1-year OS rate was similar between the two groups (69.9% vs 62.4%, p = 0.34). Using a TKa cutoff of 326 DuA, we observed a statistically significant difference in mPFS; 13.8 months in the low-TKa group (65 pts) versus 3.3 months in the high-TKa group (23 pts) (p = 0.004). The 1-year OS rate was 65.6% vs 53.3%, respectively (p = 0.18). Further data on patients treated with IT alone and with CHT-IT will be presented at the meeting. Conclusions: Our study shows a possible association between high plasma TKa levels and shorter PFS and OS in advanced NSCLC treated with first-line IT alone or combined with CHT, supporting the potential role in guiding treatment choice. Further studies are needed to validate the prognostic and predictive value of TKa in this setting. Citation Format: Maristella Giammaruco, Lorenza Landi, Mattias Bergqvist, Gabriele Minuti, Silvia Carpano, Francesca Fusco, Martina Brandi, Fabiana Letizia Cecere, Vincenzo Pio Di Noia, Livia Tosetto, Andrea Torchia, Corrado Orciuolo, Daniele Marinelli, Grisel Maver Militello, Diana Giannarelli, Federico Cappuzzo. Circulating thymidine kinase activity (TKa) as a predictive and dynamic biomarker in the metastatic non-small cell lung cancer (NSCLC): Immunoblood study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7753.

Background Hepatocellular carcinoma (HCC) is the most common form of liver cancer and a major cause of cancer-related deaths worldwide. Despite the wealth of genomics data, treatment and prognosis are still dependent on clinical and pathological factors. The molecular heterogeneity characterizing HCC is denoted by the different etiology and the related array of signaling pathways involved in tumor initiation and progression. Aberrant activation of the Wnt/β-catenin pathway is among the most frequent alterations in HCC, and stems from somatic mutations, functional over-activity of the transcription machinery and epigenetic cues. Methods Targeted DNA and RNA sequencing were combined to investigate the Wnt/β-catenin pathway and the effects of its dysregulation in the TCGA HCC cohort. For external validation, an independent cohort of78 Caucasian patients affected by HCC was used. Results We have identified a Wnt/β-catenin-related transcriptional signature denoting pathway activity regardless of the presence of pathway-related activating mutations. This model predicts survival outcomes in two independent cohorts of HCC patients (TCGA cohort, N = 177; Rome cohort, N78) and is associated with distinctive immunogenomic features. Conclusions A non-genetic state recapitulating the transcriptional footprint associated with CTNNB1 mutation identifies wild-type HCCs characterized by unfavorable survival outcomes and immune-excluded tumor immune microenvironment.

Supplementary Table S2. Matching between genomic alteration and drug proposed by MTB in ITT population.

TPS8663 Background: Most patients (pts) with EGFR-mutated (Mut) NSCLC and 1L osi treatment will eventually develop resistance. Although 1L combination strategies (osi+chemo or amivantamab+lazertinib) show potential long-term benefits, associated toxicities can impact quality of life. Temab-A, an antibody-drug conjugate with a topoisomerase 1 inhibitor payload, targets c-Met protein. MET gene amplification and c-Met protein expression are associated with poor survival outcomes in NSCLC. A Ph1 study of Temab-A in pts with refractory EGFR Mut NSCLC reported encouraging activity and a manageable safety profile (NCT05029882). Herein, we describe a Ph2/3 study of Temab-A+osi as 1L in pts with previously untreated, locally advanced or metastatic NSCLC harboring common EGFR Mut. Methods: Planned enrollment is ~194 pts in Ph2 and ~500 in Ph3 across ~200 sites in 22 countries. Adults (≥18 years) must have histologically/cytologically confirmed metastatic/locally advanced nonsquamous NSCLC with documented EGFR Mut and measurable disease by RECISTv1.1. Pts with prior EGFR tyrosine kinase inhibitor treatment in the metastatic setting are excluded. During dose escalation (Ph2), pts will receive Temab-A (1.6 or 2.4mg/kg) every 3 weeks (Q3W, 1 cycle) intravenously (IV) + 80mg osi daily. During dose expansion (Ph2), after 1 cycle of osi, pts will be randomized to receive Temab-A (1.6, 2.0, or 2.4mg/kg) Q3W IV + 80mg osi daily, or osi monotherapy, and stratified based on c-Met expression levels and history of CNS involvement. Ph2 primary objectives are safety/tolerability, efficacy as measured by objective response rate of Temab-A+osi, and determination of the recommended Ph3 dose (RP3D). Ph2 primary efficacy endpoint is objective response based on blinded independent central review assessment per RECIST v1.1. In Ph3, randomized pts will receive Temab-A+osi at RP3D or standard of care. Additional details for Ph3 will be confirmed after completion of Ph2. Clinical trial information: NCT05029882 .

Importance:For patients with advanced non-small cell lung cancer (NSCLC) and programmed cell death 1 ligand 1 (PD-L1) expression of 50% or higher, programmed cell death 1 protein or PD-L1 (PD-[L]1) inhibitor monotherapy is commonly used as first-line therapy; however, whether adding chemotherapy improves outcomes in this population remains unknown. Objective:To compare overall survival (OS) and progression-free survival (PFS) associated with PD-(L)1 inhibitor monotherapy vs chemoimmunotherapy in treatment-naive patients with advanced NSCLC and high PD-L1 expression. Data Sources:PubMed, Embase, and major oncology conference proceedings were searched for phase 3 randomized clinical trials (RCTs) published before August 3, 2025. Study Selection:Eligible studies were phase 3 RCTs that enrolled patients with untreated advanced NSCLC, evaluated PD-(L)1 inhibitor monotherapy or chemoimmunotherapy vs chemotherapy alone, and reported outcomes in patients with high PD-L1 expression. Data Extraction and Synthesis:Hazard ratios (HRs) for OS and PFS were extracted from published studies and synthesized using inverse variance methods. Additional analyses included meta-regression, network meta-analysis, and reconstructed individual patient data from published Kaplan-Meier curves. Main Outcomes and Measures:Primary outcome was OS; secondary outcome was PFS. Results:Among 24 trials including 5546 patients with PD-L1-high NSCLC, 16 evaluated chemoimmunotherapy and 8 PD-(L)1 inhibitor monotherapy. Compared with chemotherapy, survival was improved by both chemoimmunotherapy (OS: HR, 0.63 [95% CI, 0.56-0.72]; P < .001; PFS: HR, 0.44 [95% CI, 0.39-0.49]; P < .001) and PD-(L)1 inhibitor monotherapy (OS: HR, 0.74 [95% CI, 0.69-0.80]; P < .001; PFS: HR, 0.70 [95% CI, 0.65-0.76]; P < .001). Tests for subgroup differences suggested improved benefit with chemoimmunotherapy compared to PD-(L)1 inhibitor monotherapy (OS: χ21 = 4.1; P = .04; I2 = 75.8%; PFS: χ21 = 48.1; P < .001; I2 = 97.9%), consistent with meta-regression analyses (OS: HR, 0.85 [95% CI, 0.72-1.00]; P = .048; PFS: HR, 0.61 [95% CI, 0.50-0.75]; P < .001) and network meta-analyses (OS: HR, 0.85 [95% CI, 0.73-0.99]; PFS: HR, 0.61 [95% CI, 0.50-0.75]). In the reconstructed individual patient data analysis, median OS was longer with chemoimmunotherapy (n = 704 patients) compared to PD-(L)1 inhibitor monotherapy (n = 1706 patients) (29.2 months [95% CI, 25.2-35.4] vs 19.8 months [95% CI, 18.3-21.7]; HR, 0.74 [95% CI, 0.66-0.82]; P < .001). Similarly, median PFS was significantly longer with chemoimmunotherapy (n = 701 patients) compared to PD-(L)1 inhibitor monotherapy (n = 1706 patients) (11.3 months [95% CI, 10.3-13.5] vs 6.8 months [95% CI, 6.2-7.1]; HR, 0.67 [95% CI, 0.60-0.75]; P < .001). Conclusions and Relevance:In this meta-analysis of phase 3 RCTs, chemoimmunotherapy was associated with significantly improved OS and PFS compared with PD-(L)1 inhibitor monotherapy in patients with advanced NSCLC and high PD-L1 expression. Prospective trials are needed to confirm these findings.

This randomized clinical trial evaluates the efficacy and safety of tiragolumab plus atezolizumab plus chemotherapy vs placebo plus pembrolizumab plus chemotherapy in patients with advanced nonsquamous non-small cell lung cancer. QuestionCan treatment with the combination of tiragolumab plus atezolizumab plus chemotherapy improve outcomes for patients with advanced nonsquamous non-small cell lung cancer (NSCLC)?FindingsIn this phase 3 randomized clinical trial of 542 patients with previously untreated, locally advanced unresectable or metastatic NSCLC, tiragolumab plus atezolizumab plus chemotherapy did not demonstrate a progression-free or overall survival benefit vs placebo plus pembrolizumab plus chemotherapy. Tiragolumab plus atezolizumab plus chemotherapy demonstrated a safety profile that was generally similar to that of pembrolizumab plus chemotherapy.MeaningTreatment with the combination of tiragolumab plus atezolizumab plus chemotherapy did not improve outcomes for patients with advanced nonsquamous NSCLC compared with pembrolizumab plus chemotherapy. ImportanceProgrammed cell death 1 ligand 1/programmed cell death protein 1 inhibitors, with or without chemotherapy, are standard first-line treatment for patients with advanced non-small cell lung cancer (NSCLC); however, survival benefit is limited, and many patients experience disease progression.ObjectiveTo evaluate the efficacy and safety of tiragolumab plus atezolizumab plus chemotherapy vs placebo plus pembrolizumab plus chemotherapy in patients with advanced nonsquamous NSCLC.Design, Setting, and ParticipantsSKYSCRAPER-06 was a phase 3 randomized clinical trial that recruited patients with previously untreated, locally advanced unresectable or metastatic NSCLC at 129 sites in 21 countries between December 15, 2020, and September 14, 2023 (data cutoff, April 19, 2024).InterventionPatients were randomized 1:1 to receive either tiragolumab, 600 mg, plus atezolizumab, 1200 mg, plus chemotherapy (pemetrexed, 500 mg/m2, and carboplatin [area under the curve 5], or cisplatin, 75 mg/m2) or placebo plus pembrolizumab, 200 mg, plus chemotherapy via intravenous infusion on day 1 of each 21-day cycle until disease progression, loss of clinical benefit, unacceptable toxic effect, or withdrawal of consent.Main Outcomes and MeasuresPrimary end points were investigator-assessed progression-free survival and overall survival. The safety and tolerability of the study drugs were also evaluated.ResultsOf 542 patients in the full analysis set (mean [SD] age, 63.6 [9.3] years; 353 [65.1%] male), 269 were randomized to tiragolumab plus atezolizumab plus chemotherapy and 273 to placebo plus pembrolizumab plus chemotherapy. Overall, baseline demographics were similar between treatment groups. At data cutoff (median follow-up, 11.8 months), median investigator-assessed progression-free survival was 8.3 months (95% CI, 7.1-9.6 months) with tiragolumab plus atezolizumab plus chemotherapy vs 9.9 months (95% CI, 8.7-11.9 months) with placebo plus pembrolizumab plus chemotherapy (hazard ratio, 1.27; 95% CI, 1.02-1.57; P = .99); median overall survival was 18.9 months (95% CI, 15.2-23.8 months) vs 23.1 months (95% CI, 20.7-33.0 months) in each treatment group, respectively (hazard ratio, 1.33; 95% CI, 1.02-1.73; P = .98). Grade 3 to 4 adverse events occurred in 164 of 267 patients (61.4%) in the tiragolumab plus atezolizumab plus chemotherapy group and 165 of 272 patients (60.7%) in the placebo plus pembrolizumab plus chemotherapy group, with grade 5 AEs occurring in 27 of 267 patients (10.1%) and 16 of 272 patients (5.9%) in each group, respectively.Conclusions and RelevanceIn the phase 3 SKYSCRAPER-06 randomized clinical trial, the primary end points were not met and the study has been terminated.Trial RegistrationClinicalTrials.gov Identifier: NCT04619797

Supplementary Figure S1. Figure showing overall survival in the tissue only group.

PURPOSE:This analysis evaluated the influence of tissue and liquid biopsy concordance on outcomes in patients enrolled in the ROME trial. PATIENTS AND METHODS:The ROME trial, a phase II multicenter study, enrolled 1,794 patients with advanced solid tumors. Next-generation sequencing was performed on tissue and liquid biopsies using FoundationOne CDx and FoundationOne Liquid CDx. A centralized molecular tumor board reviewed results to identify actionable alterations, with 400 patients randomly assigned to tailored therapy (TT) or standard-of-care groups. TT improved objective response rate and progression-free survival (PFS) in the intention-to-treat population. Concordance was defined as the detection of the same druggable alteration in both biopsy types; discordance indicated detection in only one. RESULTS:Concordance was present in 49% of cases, with alterations detected exclusively in tissue (35%) or liquid (16%) biopsies. Patients in the concordant group receiving TT experienced improved survival outcomes. The median overall survival was 11.05 versus 7.70 months in the standard-of-care group [HR = 0.74; 95% confidence interval, 0.51-1.07], and the median PFS was 4.93 versus 2.80 months (HR = 0.55; 95% confidence interval, 0.40-0.76), respectively. In contrast, the survival benefit of TT was less pronounced or absent in patients with discordant results. Overall survival was higher in the T + L group (11.05 months), followed by tissue-only (9.93 months) and liquid-only (4.05 months) groups. PFS followed a similar pattern, with the longest PFS in the T + L group (4.93 months) versus 3.06 months in tissue-only and 2.07 months in liquid-only groups. CONCLUSIONS:The study highlights the potential value of integrating both biopsy modalities in selected clinical contexts. See related commentary by Saldanha and Siu, p. 7.

BACKGROUND:Ivonescimab has shown clinical efficacy in non-small-cell lung cancer (NSCLC). We aimed to assess the efficacy and safety of ivonescimab plus chemotherapy versus placebo plus chemotherapy in patients with advanced EGFR-mutated NSCLC whose disease progressed after third-generation EGFR tyrosine kinase inhibitor (TKI) therapy. METHODS:HARMONi is a randomised, placebo-controlled, double-blind, phase 3 trial done at 114 cancer centres and hospitals across Asia, Europe, and North America. Eligible patients were aged at least 18 years (upper limit: 75 years in Asia) with stage IIIB/IIIC or IV non-squamous EGFR-mutated NSCLC, disease progression after treatment with a third-generation EGFR-TKI, and an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned (1:1) via a centralised interactive voice response system or interactive web response system to receive ivonescimab (20 mg/kg) or placebo plus pemetrexed (500 mg/m2) and carboplatin (target area under the curve 5 mg/mL per min) intravenously every 3 weeks. Randomisation was stratified by brain metastases status at enrolment and geographical region. The primary endpoints were progression-free survival by blinded independent radiology review committee and overall survival in the intention-to-treat population. Safety was assessed in patients who received at least one dose of trial treatment. This study is registered with ClinicalTrials.gov (NCT06396065), has completed enrolment, and is ongoing for treatment and follow-up. FINDINGS:From Jan 25, 2022, to Oct 1, 2024, 660 individuals were screened for eligibility; of these, 438 were enrolled and randomly assigned to receive ivonescimab plus chemotherapy or placebo plus chemotherapy (219 per group). Of enrolled patients, 257 (59%) were female and 181 (41%) were male; 306 (70%) reported race as Asian, and 105 (24%) as White. At a median follow-up of 22·3 months (95% CI 21·5-23·0), 275 progression or death events had occurred in 345 patients (129 events among 172 patients in the ivonescimab plus chemotherapy group and 146 events among 173 patients in the placebo plus chemotherapy group). Median progression-free survival was 6·8 months (95% CI 5·7-7·1) in the ivonescimab plus chemotherapy group versus 4·4 months (4·1-5·5) in the placebo plus chemotherapy group (hazard ratio [HR] 0·52; 95% CI 0·41-0·66; p<0·0001). At a median follow-up of 29·7 months (95% CI 27·7-31·0), 262 deaths occurred in 438 patients (122 in the ivonescimab plus chemotherapy group and 140 in the placebo plus chemotherapy group). Median overall survival was 16·8 months (14·3-19·0) in the ivonescimab plus chemotherapy group versus 14·0 months (12·8-15·7) in the placebo plus chemotherapy group (HR 0·79; 0·62-1·01). The most common grade 3-4 treatment-related adverse events in the ivonescimab plus chemotherapy versus the placebo plus chemotherapy group were decreased neutrophil count (42 [19%] of 218 vs 36 [17%] of 218), decreased white blood cell count (28 [13%] vs 24 [11%]), decreased platelet count (27 [12%] vs 14 [6%]), and anaemia (22 [10%] vs 27 [12%]). Serious treatment-related adverse events occurred in 61 (28%) patients in the ivonescimab plus chemotherapy group and 33 (15%) patients in the placebo plus chemotherapy group. Treatment-related adverse events led to death in four patients (disease progression, multiple organ dysfunction syndrome, and hepatic failure, each in one patient; gastrointestinal haemorrhage and pulmonary embolism in one patient) in the ivonescimab plus chemotherapy group and five patients (pneumonitis, myocardial infarction, cerebrovascular accident, cognitive disorder, and embolic stroke, each in one patient) in the placebo plus chemotherapy group. INTERPRETATION:Ivonescimab plus chemotherapy showed a clinically meaningful and statistically significant progression-free survival benefit in patients with EGFR-mutated NSCLC after progression on EGFR-TKI therapy. The clinical benefit and lack of new safety signals of ivonescimab with chemotherapy support the potential for the combination as a new treatment option in this patient population. FUNDING:Summit Therapeutics.

BACKGROUND:Immune checkpoint inhibitor (ICI) monotherapy is the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) with PD-L1 ≥ 50%; however, up to 30% of patients experience early progression or death, including cases of hyperprogressive disease (HPD). High baseline levels (≥ 30.5%) of circulating CD10- low-density neutrophils (LDNs) have been associated with increased HPD occurrence. Emerging evidence suggests that combining ICI with platinum-based chemotherapy (PCT) may mitigate the risk of HPD. Currently, no prospective studies have addressed HPD prevention in this context. PATIENTS AND METHODS:HYPERBOLIC (NCT07274384) is a phase 2, randomized, open-label, multicenter, international trial evaluating whether adding 3 cycles of PCT to first-line cemiplimab reduces HPD rate in stage IV NSCLC with PD-L1 ≥ 50% and CD10- LDNs (identified by flow cytometry as CD15⁺CD11b⁺ within the PBMC fraction, with immature cells defined by loss of CD10) ≥ 30.5%. Seventy-four patients will be randomized (1:1 ratio) to receive cemiplimab alone or cemiplimab plus 3 PCT cycles, followed by cemiplimab maintenance. Randomization will be stratified by Lung Immune Prognostic Index. The first computed tomography scan at week 7 after treatment start will assess HPD occurrence, defined as RECIST v 1.1. disease progression with a delta tumor growth rate (ΔTGR) ≥ 50% and/or TGR ratio ≥ 2. The primary endpoint will be the combined rate of HPD and early death (death within 12 weeks with no radiological evaluation). Secondary endpoints will be HPD rate according to alternative definitions, overall survival, progression free survival, objective response rate, and safety. An extensive translational research platform will include spatial transcriptomics of tumor tissue, single-cell RNA sequencing of PBMCs, circulating-free DNA and plasma factors profiling, and saliva/stool microbiome genomics and metabolomics, to longitudinally explore tumor-host dynamic interactions during treatment. CONCLUSION:to our knowledge, HYPERBOLIC is the first prospective, biomarker-driven trial investigating early treatment escalation based on HPD risk in PD-L1-high NSCLC.

Supplementary Figure S2. Figure showing progression-free survival in the tissue only group.

Supplementary Figure S9. Differences in variant coverage between tissue and liquid tests (Venn diagram).

TPS8137 Background: Treatment options for extensive-stage small cell lung cancer (ES-SCLC) that has progressed after platinum-containing therapy with or without anti–programmed cell death protein (ligand) 1 (anti–PD-[L]1) therapy are limited. Despite the evolving treatment landscape for ES-SCLC, toxicities and poor clinical outcomes with the current globally approved standard of care (SOC), topotecan, highlight the unmet need for novel agents. Sacituzumab govitecan (SG), a Trop-2–directed antibody-drug conjugate, demonstrated encouraging antitumor activity and manageable safety as a second-line treatment for ES-SCLC in the phase 2, open-label TROPiCS-03 study. At a median study follow-up of 12.3 months in TROPiCS-03, the investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) was 42% and median overall survival (OS) was 13.6 months. Neutropenia (44%) and diarrhea (9%) were the most common grade ≥3 treatment-emergent adverse events (TEAEs), and no TEAEs led to discontinuation of SG; 1 treatment-related TEAE caused death. EVOKE-SCLC-04 (NCT06801834) is a randomized, phase 3, open-label, multicenter study evaluating the efficacy and safety of SG versus SOC (topotecan, lurbinectedin [in countries/regions where approved], or amrubicin [Japan only]) in patients with previously treated ES-SCLC. Methods: Key eligibility criteria for EVOKE-SCLC-04 include age ≥18 years, confirmed SCLC diagnosis, Eastern Cooperative Oncology Group performance status score of 0–1, measurable disease per RECIST v1.1, and disease progression after 1 prior line of platinum-containing therapy with or without anti–PD-(L)1 therapy. Prior tarlatamab treatment is allowed. Patients with untreated central nervous system (CNS) metastases and/or carcinomatous meningitis are excluded unless these are asymptomatic and immediate CNS-specific treatment is not required. Patients will be randomized 1:1 to either SG (10 mg/kg on Days 1 and 8) or SOC: topotecan (1.5 mg/m 2 daily on Days 1–5), lurbinectedin (3.2 mg/m 2 on Day 1), or amrubicin (40 mg/m 2 daily on Days 1–3) administered as intravenous infusion in 21-day cycles, until progressive disease (assessed by investigator review per RECIST v1.1), unacceptable toxicity, or death. Randomization will be stratified by chemotherapy-free interval (≥90 vs <90 days), CNS involvement (yes vs no), geographic region (East Asia vs non-East Asia), and prior anti–PD-(L)1 therapy (yes vs no). The primary endpoint is OS; secondary endpoints include progression-free survival, ORR, duration of response, patient-reported outcomes (time to first deterioration in shortness of breath and physical functioning), and safety/tolerability. This study is open and actively recruiting as of February 2025 and plans to enroll 695 patients from approximately 275 sites globally. Clinical trial information: NCT06801834 .

BACKGROUND:Subcutaneous (SC) and intravenous (IV) atezolizumab is approved for the treatment of several solid tumors. Part 2 of IMscin001 (NCT03735121) met its co-primary endpoints and demonstrated non-inferior drug exposure at cycle 1 with atezolizumab SC versus atezolizumab IV in patients with non-small cell lung cancer (NSCLC). Efficacy, safety and drug immunogenicity were similar for both atezolizumab formulations. Primary results from IMscin002 (NCT05171777) demonstrated higher preference for atezolizumab SC over atezolizumab IV amongst patients with NSCLC. We now report updated efficacy, safety and drug immunogenicity results from IMscin001 (part 2) and IMscin002. METHODS:Patients were randomized 2:1 (IMscin001) and 1:1 (IMscin002) to receive 1875 mg atezolizumab SC or 1200 mg atezolizumab IV every three weeks. In IMscin002, patients switched formulations after cycle 3 and chose a formulation for the continuation period after cycle 6. Overall survival (OS) in IMscin001, ongoing clinical benefit after cycle 16 in IMscin002, plus safety and drug immunogenicity (both studies), were secondary/exploratory endpoints. RESULTS:In IMscin001, at data cutoff (November 22, 2024), 247 patients were randomized to atezolizumab SC and 124 to atezolizumab IV; median OS was 10.9 and 10.1 months, respectively (hazard ratio: 1.00, 95% CI: 0.78-1.27). In IMscin002, at data cutoff (October 25, 2024), 179 patients were randomized, of whom 115 and 43 patients had completed the crossover and continuation periods, respectively; 65.4% (117/179) of patients had metastatic disease. Ongoing clinical benefit after cycle 16 was observed in 44.7% (80/179) of patients. In both studies, no new or unexpected safety signals were identified. The combined incidence of treatment-emergent anti-drug antibodies was 20.0% (atezolizumab SC) and 21.1% (atezolizumab IV). CONCLUSIONS:Updated results from IMscin001 (part 2) and IMscin002 show similar efficacy, safety and drug immunogenicity for atezolizumab SC and IV. No new or unexpected safety signals were reported and switching between atezolizumab formulations was well tolerated. CLINICAL TRIAL REGISTRATION NUMBER:IMscin001 (NCT03735121); IMscin002 (NCT05171777).

IntroductionThe clinical benefit of trastuzumab deruxtecan (T-DXd 5.4mg/kg), the first approved HER2-directed therapy for patients with previously treated HER2-mutant (HER2m) non-small cell lung cancer (NSCLC), was demonstrated in the phase II DESTINY-Lung02 trial. This study evaluated the efficacy of T-DXd relative to other approved treatments, including immunotherapies, vascular endothelial growth factor inhibitors, and chemotherapies, for adult patients with unresectable locally advanced or metastatic HER2m non-squamous NSCLC whose disease had progressed following ≥1 systemic therapy.MethodsA systematic literature review was conducted through September 2020 and supplemented in 2023 to identify relevant clinical trials. Given the single-intervention design in DESTINY-Lung02, two external comparator arms (ECAs) were created using docetaxel from INTEREST and VITAL, to connect T-DXd to a broader evidence network. Hazard ratios for progression-free survival (PFS) and overall survival (OS), and odds ratios (ORs) for overall response rate (ORR) were estimated via network meta-analysis. Matching adjusted indirect comparisons (MAICs) were also conducted for PFS and OS.ResultsFourteen studies with nine different regimens were included in the analysis. T-DXd showed better efficacy than all comparators, with a 100% probability of being the best treatment for PFS, ≥59% for OS, and ≥80% for ORR. Notably better PFS improvements were observed on T-DXd across all comparisons, with hazard ratios (HRs) [95% CrI] varying from 0.15 [0.09, 0.26] versus pemetrexed to 0.33 [0.20, 0.56] versus paclitaxel + bevacizumab. A similar trend was noted for OS. Patients on T-DXd maintained superior OS benefit versus other available treatments, with a notable difference demonstrated over paclitaxel + bevacizumab (HR [95% CrI]: 0.54 [0.30, 0.97]). As for ORR, the highest rate was achieved by T-DXd (49%), with odds ratios ranging from 6.09 to 21.14, representing a multifold increase compared with other regimens. Consistent results were obtained between the two different ECAs and the alternative approach via pairwise MAICs.ConclusionThis ITC suggested that T-DXd was associated with a consistent and meaningful benefit in terms of PFS and favorable OS relative to relevant comparators. For HER2m metastatic NSCLC adults, this review supports that T-DXd may be the best treatment option in the second-line or later settings.