Select NSCLC Abstracts

Abstract Number: 8026

Molecular profiling and survival in oncogene-addicted resected stage IIIAN2 non-small cell lung cancer (NSCLC): A study from the Lung ART IFCT 0503 trial.

Presenter: Victor Albarran-Artahona
Session: Lung Cancer—Non–Small Cell Local-Regional/Small Cell/Other Thoracic Cancers

ABSTRACT Background: Molecular profiling is standard-of-care in metastatic NSCLC and increasingly important in earlier stages as personalized approaches arise. The role of adjuvant radiotherapy (ART) in oncogene-addicted, fully-resected stage IIIAN2 NSCLC remains undefined.

Methods:

The LungART trial (NCT00410683) randomized 501 patients (pts) with resected stage IIIAN2 NSCLC (AJCC 7th ed.) to ART or observation. No disease-free survival (DFS) benefit was found for ART. For consenting pts, a tumor block was collected. A histological central review was performed in all cases. Molecular profiling was conducted by Whole transcriptome sequencing (WTS; mRNA capture with Agilent exome lit and Illumina NovaSeq 6000 S4 Reagent Kit v1.5-300 cycles paired sequencing) to identify relevant alterations, with findings treated as per standard procedures.

Results:

282 pts had available samples, from which 50% received ART. 90% were current or former smokers. Baseline characteristics were well balanced (table 1). After review, 79% of pts were classified as non-squamous cell carcinoma. TP53 was the most common mutation (mut) identified (46%). Targetable mutations included KRAS p.G12C (8.8%), EGFR-sensitizing -exon 19 in-frame deletion and L858R mut- (3.5%), and BRAF p.V600 (1.4%). Non p.G12C KRAS mut were found in 28 pts, while atypical EGFR mut including exon 20 insertion, and non V600 BRAF were identified in 3.1% and 2.8% of pts, respectively. A ERBB2 exon 20 insertion mut was identified in one case. STK11 and KEAP1 mutation were identified in 5.3% and 3.5% of pts, respectively. No translocations were detected. In the STK11 mut subgroup, a significant difference in DFS (p=0.032) and OS (p=0.0043) was observed. No differences in outcomes were observed for other major molecular alterations nor between treatment arms, including TP53 (p=1.0 and 0.86 for DFS and OS, respectively).

Conclusions:

Our study did not found a significant outcomes difference among major oncogenic-driven alterations, probably due to population characteristics and small representation of oncogene addicted subgroups. Our findings confirm STK11 as a poor prognostic factor in resected stage IIIAN2 NSCLC. Of note, TP53 did not show any impact on survival. Further studies are needed to confirm these observations and explore its implications.

Baseline characteristics.

Characteristic	ART¬† ¬†N=141	Observation¬† N=139
Age	61 (54-68)	61 (55-66)
Gender
¬†¬†¬†Female	44 (31%)	42 (30%)
¬†¬†¬†¬†Male	97 (69%)	97 (70%)
Neoadj. ChT	22 (16%)	23 (17%)
Adj. ChT	120 (85%)	120 (86%)
Smoking
¬†¬†¬†¬†Current	16 (11%)	14 (10%)
¬†¬†¬†¬†Former	110 (78%)	112 (81%)
¬†¬†¬†¬†Never	15 (11%)	13 (9.4%)
Major molecular alterations	¬†	¬†
¬†¬†¬†¬†¬† TP53	67 (47%)	65 (46%)
¬†¬†¬†¬†¬† KRAS p.G12C	16 (11%)	9 (6.4%)
¬†¬†¬†¬†¬† KRAS non-p.G12C	14 (9.9%)	14 (10%)
¬†¬†¬†¬†¬† EGFR sensitizing	4 (2.8%)	6 (4.3%)
¬†¬†¬†¬†¬† EGFR (others)	3 (2.1%)	6 (4.3%)
¬†¬†¬†¬†¬† STK11	6 (4.3%)	9 (6.5%)
¬†¬†¬†¬†¬† KEAP1	6 (4.3%)	4 (2.9%)
¬†¬†¬†¬†¬† BRAF p.v600	0 (0%)	3 (2.1%)
¬†¬†¬†¬†¬† BRAF non-p.V600	6 (4.2%)	3 (2.1%)

Summary of Study Impact on IBTROZI:

Limited relevance. The study focuses on resected stage IIIAN2 NSCLC and does not address ROS1-positive NSCLC or the use of ROS1 inhibitors like IBTROZI. The findings are more relevant to understanding prognostic factors in a surgically resected population rather than impacting the therapeutic landscape for advanced ROS1-positive NSCLC.

Clinical Readout:

Setting and population: Resected stage IIIAN2 NSCLC, not advanced or metastatic; no ROS1 fusion detection or CNS disease status reported; focus on molecular profiling post-surgery.
Efficacy signals: No significant DFS or OS benefit from ART; significant DFS and OS differences in STK11 mutation subgroup.
Safety/tolerability: Not reported.
Strength of evidence: Phase III, 501 patients, randomized control, limitations include small representation of oncogene-addicted subgroups.

Competitive Considerations:

This regimen does not compete directly with IBTROZI in frontline ROS1+ NSCLC or after 1 prior ROS1 TKI.
Does not change sequencing norms versus other ROS1 inhibitors or chemo-based options.
No subpopulations identified where IBTROZI becomes more or less attractive.

Clinical or Market Strategy Implications:

Medical Affairs: Focus on the prognostic implications of STK11 mutations; monitor for further studies that might explore these findings in advanced settings.
Label and evidence strategy: No new endpoints or sequencing studies suggested for IBTROZI based on this study.
Access and adoption: No practical advantages or pathway implications for IBTROZI inferred from this study.

What would change your conclusion:

Missing data point #1: ROS1 fusion status and outcomes in this population.
Missing data point #2: CNS disease status and intracranial efficacy data.
Decision trigger: Significant findings in ROS1-positive or CNS disease settings that could impact IBTROZI's positioning.

Link to Abstract 8026

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Abstract Number: 8063

Neoadjuvant hypofractionated radiotherapy plus tislelizumab with anlotinib followed by adjuvant tislelizumab with anlotinib in patients with resectable non-small cell lung cancer (NSCLC): Preliminary analysis of a phase II trial (NEO-PIONEER).

Presenter: Min Fang
Session: Lung Cancer—Non–Small Cell Local-Regional/Small Cell/Other Thoracic Cancers

ABSTRACT Background: Although neoadjuvant immune checkpoint inhibitors (ICIs) combined with chemotherapy is the current standard of care for resectable NSCLC, the optimal combination strategy to improve efficacy with low toxicity remains to be explored. Preclinical and clinical studies have shown that anti-angiogenic therapy can enhance the efficacy of immunotherapy and sensitize radiotherapy through a variety of mechanisms. We designed a trial to test the activity of triple therapy of radiotherapy, angiogenesis inhibitors and ICIs for resectable NSCLC.

Methods: This is a prospective, single-arm, phase II (NCT06379087) to explore the efficacy and safety of hypofractionated radiotherapy followed by sequential tislelizumab and anlotinib in the perioperative treatment of resectable NSCLC. A total of 20 eligible patients aged 18 years or older, with histologically confirmed stage II/IIIA resectable NSCLC, and without prior systemic anticancer treatment or known EGFR mutations, ALK rearrangements or ROS1 fusions are enrolled. The treatment regimen involved hypofractionated radiotherapy on d1-3 (24 Gy/3 fractions), followed by tislelizumab plus anlotinib within 1 week for 2 cycles after radiotherapy. Patients without disease progression after two cycles were followed by surgical resection within 4-6 weeks after the last dose of neoadjuvant treatment, and receive adjuvant treatment with tislelizumab plus anlotinib after surgery up to 1 year. The primary endpoint was pCR rate. And the secondary endpoint was MPR rate, 1-year EFS rate and the incidence of treatment-related AE.

Results: Between May 1, 2024, and December 31, 2024, a total of 10 patients were enrolled. 6 (60%) of them had pathological stage IIIA. All patients enrolled have completed radiotherapy and 2 cycles of neoadjuvant treatment with tislelizumab plus anlotinib. 1 patient experienced disease progression following neoadjuvant and did not receive surgery. 7 patients have underwent surgery. While 2 patients were waiting surgery. Among the 7 patients who underwent surgery, 5 (71.4%) of 7 patients achieved pCR, all 7 patients demonstrated a MPR. In terms of safety, 1 patient experienced grade 3-4 treatment related adverse events, which was alanine aminotransferase and aspartate aminotransferase. There were no treatment-related deaths reported during the study period.

Conclusions: Preoperative hypofractionated radiotherapy followed by immunotherapy and anti-angiogenesis therapy is tolerable, leads to a clinically significant pCR.

Summary of Study Impact on IBTROZI:

Limited relevance. The study focuses on resectable NSCLC without ROS1 fusions, which does not directly impact IBTROZI's positioning in advanced ROS1-positive NSCLC.

Clinical Readout:

Setting and population: Resectable NSCLC, stage II/IIIA, no prior systemic treatment, no ROS1 fusions, CNS status not reported.
Efficacy signals: pCR achieved in 71.4% of patients who underwent surgery; MPR in all surgical patients; 1-year EFS rate not reported.
Safety/tolerability: Grade 3-4 AEs in 1 patient (elevated liver enzymes); no treatment-related deaths.
Strength of evidence: Phase II, single-arm, small sample size (10 patients), no control group, early-stage data.

Competitive Considerations:

This regimen does not compete directly with IBTROZI in frontline ROS1+ NSCLC or after 1 prior ROS1 TKI.
Does not change sequencing norms versus other ROS1 inhibitors or chemo-based options.
No subpopulations where IBTROZI becomes more or less attractive based on this study.

Clinical or Market Strategy Implications:

Medical Affairs: Focus on differentiating IBTROZI in advanced ROS1+ NSCLC; monitor for emerging data on ROS1+ resectable NSCLC if relevant.
Label and evidence strategy: No new endpoints or studies suggested by this abstract for IBTROZI.
Access and adoption: No practical advantages or pathway implications for IBTROZI based on this study.

What would change your conclusion:

Missing data point #1: ROS1 fusion status in a similar study setting.
Missing data point #2: CNS disease outcomes in ROS1+ populations.
Decision trigger: Significant efficacy or safety data in ROS1+ resectable NSCLC that could inform IBTROZI's use in earlier stages.

Link to Abstract 8063

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Abstract Number: 8065

Initial results of a screening trial for evaluating oncogenic drivers in Japanese patients with surgically resected early-stage non-small cell lung cancer: LC-SCRUM-Advantage.

Presenter: Yuki Matsumura
Session: Lung Cancer—Non–Small Cell Local-Regional/Small Cell/Other Thoracic Cancers

ABSTRACT Background: The LC-SCRUM-Advantage is a screening trial to evaluate oncogenic drivers in patients with surgically resected early-stage non-small cell lung cancer (NSCLC). Recent clinical trials, such as the ADAURA and ALINA trials, have demonstrated the efficacy of molecular targeted therapy as adjuvant therapy following surgery for patients with early-stage NSCLC harboring oncogenic drivers. Our study aims to determine the proportion of early-stage NSCLC with any actionable oncogenic drivers that are candidates for adjuvant targeted therapy. This abstract presents the initial data collected until Dec 2024.

Methods: Patients with operable clinical stage I to III NSCLC were eligible for this study. Surgical tumor samples were collected post-surgery, and genomic analysis of oncogenic drivers was centrally evaluated using a next-generation sequencing system, the Oncomine Precision Assay, which targets 50 gene alterations. PD-L1 immunohistochemistry using the 22C3 antibody was also performed on the submitted tumor samples. If possible, preoperative biopsy tumor samples were also collected and evaluated using the AmoyDx Pan Lung Cancer PCR Panel. An actionable oncogene was defined as EGFR, ALK, ROS1, KRAS, BRAF, HER2, RET, MET, NRG1, or NTRK genes.

Results: Between August 2022 and December 2024, 646 patients were enrolled in the LC-SCRUM-Advantage. Among them, 57% had stage I, 27% had stage II, 16% had stage III, and 71% had adenocarcinoma histology. Of the 591 evaluable patients in this analysis, an actionable oncogenic driver was found in 46% of cases (274/591). Identified oncogenic drivers included 190 (24%) EGFR mutations (89 L858R, 77 ex19del, 10 ex20ins, 14 uncommon), 26 (4%) MET ex14 skipping, 20 (3%) KRAS G12C, 18 (3%) HER2 mutations (including ex20ins), 7 (1%) ALK fusion, 5 (1%) NRG1 fusion, 4 (1%) BRAFV600E, 2 (<1%) RET fusions, 1 (<1%) ROS1 fusion, and 1 (<1%) NTRK fusion. PD-L1 expression was observed in 19% for >50%, 40% for 1-49%, and 41% for <1%. Among patients with paired tumor samples from surgery and preoperative biopsy, the concordance rate of detected actionable oncogenic drivers was 95%.

Conclusions: Our study found actionable oncogenic drivers in 46% of Japanese patients with surgically resected early-stage NSCLC. Based on historical control, the proportion of any oncogenic drivers in early-stage NSCLC is similar to that in advanced NSCLC. Comprehensive genomic screening of patients with early-stage NSCLC will accelerate the development of clinical trials for adjuvant-targeted therapy.

Summary of Study Impact on IBTROZI:

Limited relevance. The study focuses on early-stage NSCLC and the identification of oncogenic drivers for adjuvant therapy, which does not directly impact IBTROZI's positioning in advanced ROS1-positive NSCLC.

Clinical Readout:

Setting and population: Early-stage NSCLC, stages I-III, post-surgical resection, ROS1 fusion detected in <1% of cases, no CNS baseline status reported, no prior therapies relevant to IBTROZI's setting.
Efficacy signals: Not reported.
Safety/tolerability: Not reported.
Strength of evidence: Screening trial, 646 patients enrolled, genomic analysis using Oncomine Precision Assay, no direct treatment outcomes reported.

Competitive Considerations:

This regimen does not compete directly with IBTROZI in frontline ROS1+ NSCLC or after 1 prior ROS1 TKI.
Does not change sequencing norms versus other ROS1 inhibitors or chemo-based options.
No subpopulations identified where IBTROZI becomes more or less attractive.

Clinical or Market Strategy Implications:

Medical Affairs: Focus on the importance of genomic screening in early-stage NSCLC; monitor developments in adjuvant therapy trials.
Label and evidence strategy: No new endpoints or sequencing studies suggested for IBTROZI based on this study.
Access and adoption: No practical advantages or pathway implications for IBTROZI inferred from this study.

What would change your conclusion:

Missing data point #1: Efficacy outcomes specific to ROS1-positive patients in early-stage NSCLC.
Missing data point #2: CNS disease status and outcomes in the study population.
Decision trigger: Significant findings in early-stage ROS1-positive NSCLC that suggest a shift in treatment paradigms or new adjuvant therapy strategies.

Link to Abstract 8065

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Abstract Number: 8538

Clinical outcomes and characterization of HER2 alterations in non-small cell lung cancer (NSCLC).

Presenter: Nikita Dahake
Session: Lung Cancer—Non-Small Cell Metastatic

ABSTRACT Background:

Subsets of NSCLC carry alterations in the human epidermal growth factor receptor 2 (HER2) gene such as mutations (mt), amplification (amp), and protein overexpression. These alterations reflect distinct patient (pt) populations and disease biology, translating to variable outcomes with immunotherapy +/- chemotherapy. HER2-directed therapies have shown significant efficacy for HER2 mt and to a lesser extent HER2 3+ NSCLC. We describe the genomic landscape of HER2-altered NSCLC in a large cohort of tumors from the Caris database and explore pt outcomes.

Methods:

Next-generation sequencing of DNA (592-gene or WES) and RNA (WTS) was performed on NSCLC samples (n=52,690, Caris Life Sciences, Phoenix, AZ). IHC was performed on FFPE sections (HER2 staining intensity of 2+, >5%). HER2 amp was defined as copy number > 6. Tumor microenvironment studies were calculated by QuantiSeq. Significance was calculated using chi-square, Fisher‚Äôs exact, or Mann-Whitney U test, with p-values adjusted for multiple comparisons (q<0.05). Overall survival (OS) was estimated from insurance claims data using Cox proportional hazards model to calculate hazard ratio (HR) and log-rank tests to calculate P values.

Results:

670 tumors were HER2 mt (N=492 within the kinase domain, 133 extracellular domain, 47 transmembrane domain, 16 other, 400 HER2 amp, and 272 HER2 IHC 2+. Treatment (tx) received prior to tumor sample collection is not reported in 64.2% HER2 mt, 68.8% HER2 2+, 56.5% HER2 amp (may reflect tx naive pts). Among female pts, HER2 mt was more common than amp or overexpressed 3+ (59.7% vs. 39.8% vs 36.2% p<0.01). HER2 mt correlated with improved OS compared to HER2 amp and a cohort of NSCLC driverless tumors (wild type EGFR, ALK, ROS1, RET, KRAS, and HER2). When compared to ROS1+, ALK+ and EGFR mt, HER2 mt had shorter OS (Table). Higher frequency of co-mts are noted in HER2 amp vs mt, including TP53 (90% vs 57%), EGFR (10% vs 6%), SMARCA4 (12% vs 5%), CDKN2A (16% vs 5%), NKX2-1 (2% vs 0.5%) and TMB-H (47% vs 21%), all p<0.001. No differences in PD-L1 expression were observed. Higher frequency of co-mts for HER2 IHC 2+ vs HER2 mt, including KRAS (33% vs 3%), KEAP1 (21% vs 7%), BRAF (5% vs 0.8%), EGFR (13% vs 6%) and SMARCA4 (11% vs 5%), all p<0.001. HER2 mt tumors had greater infiltration of NK cells, B cells, M2 macrophages, neutrophils and Tregs (FC 1.2-1.3) vs. HER2 IHC 2+.

Conclusions:

This study highlights the significant differences in OS and co-alterations for HER2 mt vs other HER2 altered and NSCLC driverless tumors. This data confirms the unmet need to further explore these differences to optimize tx and improve OS.

NSCLC cohorts compared to HER2 mt cohort (22.0 months).

NSCLC Cohort	Survival (months)	HR, 95% CI	p-value
HER2 amp	12.3	0.67 (0.57-0.79)	<0.001
HER2 2+	14.1	0.92 (0.77-1.09)	0.33
Driverless	16.2	0.85 (0.77-0.94)	<0.01
ROS1 fusion	35.3	1.3 (1.0-1.7)	0.02
ALK fusion	47.4	1.9 (1.6-2.3)	<0.001
EGFR mt	30.7	1.3 (1.2-1.5)	<0.001

Summary of Study Impact on IBTROZI:

Limited relevance. The study focuses on HER2-altered NSCLC, which is outside the direct setting of ROS1-positive NSCLC where IBTROZI is positioned. Bridging evidence would be needed to establish relevance to IBTROZI's strategic positioning.

Clinical Readout:

Setting and population: Advanced NSCLC with HER2 alterations; not directly related to ROS1-positive NSCLC. CNS baseline status and prior therapies not reported.
Efficacy signals: Overall survival (OS) differences among HER2-altered subtypes; ROS1 fusion cohort reported with 35.3 months OS, but not the focus of the study.
Safety/tolerability: Not reported.
Strength of evidence: Retrospective analysis of a large cohort (n=52,690); limitations include lack of treatment history for a significant portion of patients.

Competitive Considerations:

This regimen does not compete directly with IBTROZI in frontline ROS1+ NSCLC or after 1 prior ROS1 TKI.
Does not change sequencing norms versus other ROS1 inhibitors or chemo-based options.
No subpopulations identified where IBTROZI becomes more or less attractive based on this study.

Clinical or Market Strategy Implications:

Medical Affairs: Focus on differentiating IBTROZI's efficacy in ROS1+ NSCLC; monitor for emerging data on HER2 and ROS1 co-alterations if relevant.
Label and evidence strategy: No new endpoints or studies suggested by this study for IBTROZI.
Access and adoption: No direct implications for IBTROZI's pathway or payer strategies.

What would change your conclusion:

Missing data point #1: Direct comparison of ROS1+ NSCLC outcomes with HER2-altered NSCLC.
Missing data point #2: Detailed treatment history and CNS status for ROS1+ patients.
Decision trigger: Significant differences in durability, CNS control, or tolerability in ROS1+ NSCLC that could impact practice.

Link to Abstract 8538

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Abstract Number: 8563

Clinical outcomes and predictors of response to PD-(L)1 blockade in patients with oncogene-driver negative NSCLC who have never smoked.

Presenter: Eleonora Gariazzo
Session: Lung Cancer—Non-Small Cell Metastatic

ABSTRACT Background: Non-small cell lung cancer (NSCLC) in patients (pts) who have never smoked is associated with poor response to immune checkpoint inhibitors (ICI). However, most studies have focused on pts with actionable oncogenes (e.g., EGFR, ALK, ROS1, RET, MET), and it remains unclear whether specific clinicopathologic and genomic features can predict ICI response in those without these actionable drivers.

Methods: Clinicopathologic characteristics and outcomes data were collected from pts with metastatic, oncogene driver-negative, NSCLC who received ICI across 5 academic cancer centers in US and EU. Single sample gene set enrichment analysis was performed on NSCLC samples from the Stand Up To Cancer (SU2C) cohort to characterize transcriptomic correlates of response to ICI monotherapy in responders and non-responders.

Results: Of 5639 pts with metastatic NSCLC analyzed, 708 (12.6%) tested negative for actionable oncogene drivers and had never smoked. Among these, median age was 64 years, 59.5% were women, 65.2% had ECOG PS 0/1, and 83.8% had adenocarcinoma. At a median follow-up of 36.9 months (mo), objective response rate (ORR) was 21.8%, median progression-free survival (mPFS) was 4.5 mo, and median overall survival (mOS) was 16.9 mo in this patient population. Pts with PD-L1 TPS ‚â•1% had significantly higher ORR (31.1% vs. 16.1%, p<0.01), and longer mPFS (HR 0.74, p<0.01) compared to those with PD-L1 <1%. Similarly, pts with very high TMB (‚â•90^th percentile) had higher ORR (52.2% vs 22.8%, p<0.01), longer mPFS (HR 0.50, p<0.01), and mOS (HR 0.40, p<0.01) compared to those with a TMB <90^th percentile. Pts with positive PD-L1 expression ‚â•1% and very high TMB had the highest ORR and the longest mPFS and mOS compared to pts with either one of these biomarkers alone. Treatment outcomes also varied by regimen: pts receiving dual PD-(L)1+CTLA-4 blockade or PD-(L)1 blockade + chemotherapy had higher ORR compared to those receiving PD-(L)1 monotherapy (30.0% vs 36.5% vs 10.3%, respectively, p<0.01). Dual PD-(L)1+CTLA4 inhibition was also associated with significantly longer mPFS (9.4 vs 6.9 vs 2.9 mo, p<0.01) and mOS (47.5 vs 19.7 vs 14.7 mo, p<0.01) compared to PD-(L)1 + chemotherapy and PD-(L)1 monotherapy, respectively. These differences were validated in pts receiving these regimens as first-line therapy. In NSCLC samples from pts who had never smoked without oncogenic driver mutations in the SU2C cohort, responders to ICI showed upregulation of innate and adaptive immune responses pathways, including enhanced MHC I/II antigen presentation, as well as increased T-cell activation, proliferation, and chemotaxis.

Conclusions: These results emphasize how PD-L1‚â•1%, very high TMB, and use of dual checkpoint blockade are associated with improved outcomes in pts who have never smoked with oncogene-driver negative NSCLC, aiding personalized ICI use in this neglected population.

Summary of Study Impact on IBTROZI:

Limited relevance. The study focuses on immune checkpoint inhibitors in oncogene driver-negative NSCLC, which does not directly impact IBTROZI's positioning in ROS1-positive NSCLC.

Clinical Readout:

Setting and population: Metastatic NSCLC, oncogene driver-negative, never-smokers, PD-L1 and TMB status assessed, no ROS1 focus.
Efficacy signals: ORR 21.8%, mPFS 4.5 months, mOS 16.9 months; higher efficacy with PD-L1 ≥1% and high TMB.
Safety/tolerability: Not reported.
Strength of evidence: Retrospective analysis, 5639 patients, multi-center, no control group, focused on ICI response.

Competitive Considerations:

This regimen does not compete directly with IBTROZI in frontline ROS1+ NSCLC or after 1 prior ROS1 TKI.
Does not change sequencing norms versus other ROS1 inhibitors or chemo-based options.
No subpopulations where IBTROZI becomes more or less attractive based on this study.

Clinical or Market Strategy Implications:

Medical Affairs: Focus on differentiating IBTROZI's efficacy in ROS1+ NSCLC, especially in CNS disease and resistance mutations.
Label and evidence strategy: No new endpoints or studies suggested by this abstract for IBTROZI.
Access and adoption: No practical advantages or pathway implications for IBTROZI from this study.

What would change your conclusion:

Missing data point #1: ROS1-positive NSCLC outcomes with ICI.
Missing data point #2: CNS disease outcomes in ROS1-positive NSCLC with ICI.
Decision trigger: Significant efficacy or safety data in ROS1-positive NSCLC with ICI that challenges current ROS1 TKI standards.

Link to Abstract 8563

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Abstract Number: 8564

Efficacy and safety of metronomic oral vinorelbine combined with PD-1 inhibitors as first-line therapy in advanced non-small-cell lung cancer in elderly patients.

Presenter: Lin Li
Session: Lung Cancer—Non-Small Cell Metastatic

ABSTRACT Background:

Elderly individuals aged over 70 constitute the majority of Non-small cell lung cancer(NSCLC) patients. However, their poor general status, multiple co-morbidities, and limited social support present significant challenges in antitumor treatments, especially standard platinum-based chemotherapy. Metronomic chemotherapy (MCT) involves the regular administration of chemotherapy drugs at low doses, offering improved safety, anti-angiogenic tumor effects, and immune modulation compared to conventional chemotherapy. In light of these considerations, we have designed a phase II trial to evaluate the efficacy and safety of PD-1 inhibitors plus metronomic oral vinorelbine (mOV) as first-line therapy for elderly patients with metastatic NSCLC.

Methods:

Elderly patients(‚â•70 years) with previously untreated locally advanced or metastatic NSCLC without a sensitising EGFR mutation, ALK fusion or ROS1 fusion and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 were recruited for this study. Patients received PD-1 inhibitors combined with mOV (30mg, TIW1, day 1-3-5 per week) for 6 cycles, followed by PD-1 inhibitors maintenance until disease progression or intolerable toxicities. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety profiles.

Results:

From March 2021 to November 2024, 37 patients were enrolled in the study. The median age was 77 with 31 (83.8%) males. Median follow-up time was 13.5 months (range 1.8 months-44.7 months). The median PFS was 10.9 months (95%Cl: 1.0 months-20.9 months) and the median OS was 26.2 months (95%Cl: (6.7 months-45.7 months). The ORR and DCR were 33.3% (95%C1: 17.3%-47.5%) and 86.1% (95%Cl: 71.9%-95.7%), respectively. Compared to those with low PD-L1 expression (PD-L1 TPS <50%), patients with high PD-L1 expression (PD-L1 TPS ‚â•50) had significant prolonged PFS [mPFS=6.1 months vs 23.0 months, p=0.01, HR = 0.19 (95%CI 0.05-0.69)] and OS [mOS=6.1 months vs not reached, p=0.02, HR = 0.09 (95%CI 0.01-0.70)]. Adverse events (AEs) of any grade were observed in 29 (78.4%) patients of which immune-related adverse events (irAEs) occurred in 14 (37.8%) patients. Grade 3-4 adverse reactions were reported in 5 (13.5%) patients, 4 of which were irAEs, including immune-associated pneumonia, myocarditis, myositis, enteritis and hepatitis. No grade 5 adverse events were reported.

Conclusions:

The regimen of PD-1 inhibitors plus mOV as first-line therapy showed significant survival benefits and a favorable safety profile in elderly patients with driver-gene-negative metastatic NSCLC, particularly those with high PD-L1 expression.

Summary of Study Impact on IBTROZI:

Limited relevance. The study focuses on a different patient population (elderly, driver-gene-negative NSCLC) and does not address ROS1-positive NSCLC, which is the target population for IBTROZI.

Clinical Readout:

Setting and population: Elderly patients (≥70 years) with untreated locally advanced or metastatic NSCLC, excluding ROS1 fusions; ECOG 0-1; no CNS disease status reported.
Efficacy signals: Median PFS 10.9 months, median OS 26.2 months; ORR 33.3%, DCR 86.1%; significant PFS and OS benefit in high PD-L1 expression subgroup.
Safety/tolerability: Grade 3-4 AEs in 13.5% of patients, primarily immune-related; no grade 5 AEs reported.
Strength of evidence: Phase II, 37 patients, single-arm, limited by small sample size and lack of control group.

Competitive Considerations:

This regimen does not compete directly with IBTROZI in frontline ROS1+ NSCLC or after 1 prior ROS1 TKI, as it targets a different genetic profile.
Does not change sequencing norms versus other ROS1 inhibitors or chemo-based options for ROS1+ NSCLC.
No direct impact on IBTROZI's attractiveness in subpopulations such as CNS disease or resistance mutations.

Clinical or Market Strategy Implications:

Medical Affairs: Focus on differentiating IBTROZI's efficacy in ROS1+ populations; monitor emerging data on PD-1 inhibitors in NSCLC.
Label and evidence strategy: No new endpoints or studies suggested for IBTROZI based on this study.
Access and adoption: No direct implications for IBTROZI; focus remains on ROS1+ NSCLC population.

What would change your conclusion:

Missing data point #1: ROS1-positive NSCLC outcomes with similar regimens.
Missing data point #2: CNS disease outcomes in ROS1+ populations.
Decision trigger: Significant efficacy or safety data in ROS1+ NSCLC that could influence treatment sequencing.

Link to Abstract 8564

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Abstract Number: 8604

Osimertinib plus repotrectinib phase I trial in TKI-resistant non-small cell lung cancer (NSCLC) with EGFR mutations.

Presenter: Andrés Aguilar Hernandez
Session: Lung Cancer—Non-Small Cell Metastatic

ABSTRACT Background: NSCLC patients with EGFR mutations develop resistance when treated with EGFR TKI. We previously reported that osimertinib combined with TPX-0005 (repotrectinib) ablated STAT3, paxillin, and YAP1 phosphorylation in a preclinical model. Osimertinib-induced Src and FAK phosphorylation was abrogated with TPX-0005 alone or in combination with osimertinib in H1975 (EGFR L858 and T790M) cell line. TPX-0005 potentiated the effect of osimertinib in PC9 and H1975 tumor xenografts without substantial toxicity (Karachaliou et al. eBioMedicine 2017). The findings prompted us to carry out the current study with osimertinib plus TPX-0005, which inhibit Src/FAK/JAK2, in addition to ALK, ROS1 and NTRKs.

Methods: TOTEM (NCT04772235) is a phase I, two-part study to assess safety, tolerability, pharmacokinetics, and antitumor activity of repotrectinib plus osimertinib in EGFR-mutant patients resistant to previous lines of treatment. Phase Ia was a dose escalation (3+3). Treatment na√Øve patients were treated with osimertinib 80mg QD plus: repotrectinib 80mg QD, 160mg QD and 160mg BID. In part Ib, patients should have received osimertinib or osimertinib plus chemotherapy as first line treatment. Results from part Ia are presented in this abstract.

Results: Phase Ia included 15 patients with a median age of 61 yrs (34-71). Of these patients:10 were female (66.7%), 9 had PS1 (60%), and 7 had brain metastasis (48.7%). At the time of starting treatment, two patients had exon 18 (G719X) mutations (p.E709_T710delinsD and p.G719A), 5 had exon 21 (4 p.L858R, 1 p.L861Q) and 8 had exon 19 deletion. Eight patients had p53 co-mutations, other co-alterations included PIK3CA, RET, FAT1, FGFR3 and MYC mutations, CDK4 and EGFR amplification, and MET, ROS1, EGFR and FGFR3 over-expression. Six patients were treatment-naive, four were osimertinib progressors, and five had received two or more previous lines of treatment. With repotrectinib plus osimertinib, intracranial complete response was attained in 3 of the seven patients with brain metastasis (42.85%). The overall objective response rate (ORR) was noted in 5 patients (33.3%), and stable disease in 8 patients (53.3%). Median PFS was 4.4 mo. (95% CI 2.9-NR). Among the adverse events, transient, manageable dizziness was observed in 76% of the patients, and dysgeusia occurred in 48% of cases. Most side effects were grade 1-2, including anemia, diarrhea, fatigue, and liver enzyme elevation. Pharmacokinetic analysis indicated a favorable profile of the combination. Dose level 3 (160mg BID) was safe, therefore, part Ib continued with repotrectinib 160mg BID plus osimertinib 80mg QD in 15 patients enrolled.

Conclusions: In Part Ia osimertinib + repotrectinib showed impressive intracranial ORR with a manageable safety profile. Part Ib with repotrectinib 160 mg BID plus osimertinib 80 mg is ongoing. Updated results will be presented.

Summary of Study Impact on IBTROZI:

Limited relevance. The study focuses on EGFR-mutant NSCLC resistant to prior treatments, not directly on ROS1-positive NSCLC, which is IBTROZI's target indication.

Clinical Readout:

Setting and population: Advanced EGFR-mutant NSCLC, post-EGFR TKI resistance, with some patients having brain metastases; not directly relevant to ROS1-positive NSCLC.
Efficacy signals: Intracranial ORR of 42.85% in patients with brain metastases; overall ORR of 33.3%; median PFS of 4.4 months.
Safety/tolerability: Mostly grade 1-2 AEs, including dizziness (76%) and dysgeusia (48%); manageable safety profile.
Strength of evidence: Phase I, small sample size (15 patients), single-arm, early-stage results with ongoing part Ib.

Competitive Considerations:

This regimen does not compete directly with IBTROZI in frontline ROS1+ NSCLC or after 1 prior ROS1 TKI, as it targets a different mutation (EGFR).
Does not change sequencing norms versus other ROS1 inhibitors or chemo-based options for ROS1-positive NSCLC.
No direct impact on IBTROZI's attractiveness in subpopulations such as CNS disease or resistance mutations specific to ROS1.

Clinical or Market Strategy Implications:

Medical Affairs: Monitor for any emerging data on repotrectinib's activity in ROS1-positive settings, though current focus is on EGFR mutations.
Label and evidence strategy: No immediate implications for IBTROZI; focus remains on ROS1-specific endpoints and resistance management.
Access and adoption: No direct impact on IBTROZI's pathway or payer considerations given the different target mutation.

What would change your conclusion:

Missing data point #1: Evidence of repotrectinib's efficacy in ROS1-positive NSCLC.
Missing data point #2: Comparative data on intracranial efficacy in ROS1-positive patients.
Decision trigger: Significant efficacy or safety data in ROS1-positive NSCLC that could influence treatment sequencing or choice.

Link to Abstract 8604

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Abstract Number: 8628

Association of circulating tumor DNA (ctDNA) variant allelic frequency (VAF) with outcomes on matched targeted therapies (TT) in advanced non-small cell lung cancer (aNSCLC).

Presenter:
Session:

ABSTRACT Background: There is a critical gap in our understanding of the correlation between ctDNA driver VAF and outcomes in patients (pts) with aNSCLC treated with TT. We explore the landscape of driver alterations (alts) in aNSCLC by ctDNA VAF and assess the association with outcomes in pts treated with matched TT.

Methods: We analyzed 3,146 pts with aNSCLC with a driver positive liquid biopsy (LBx) (FoundationOneLiquid CDx) Targetable driver alts were defined as alts listed in NCCN guidelines and were stratified by VAF. Clinical outcomes were assessed for pts included in the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine aNSCLC clinico-genomic database (FH-FMI CGDB) originating from approximately 280 US cancer clinics (~800 sites of care). For 224 pts receiving matched TT within 60 days of LBx collection, multivariate Cox proportional hazard models were employed to evaluate the association of VAF on real-world progression-free (rwPFS) and overall (rwOS) survival adjusting for clinical and demographic factors.

Results: Among 3,146 pts with targetable alts detected in LBx, the frequency of drivers with VAF <1% in ctDNA was 36% (1,185/3,262 alts). Distribution of drivers by VAF is shown in the table. For pts in the FH-FMI CGDB treated with matched TT following driver positive LBx, clinical and demographic characteristics were balanced between pts with driver VAF <1% (n = 75) and those with VAF ‚â•1% (n = 147), except for the presence of liver metastases, which were more common in pts with VAF <1% (12% v 26%; p = 0.0002). There was no significant difference in the median rwPFS for pts with driver VAF <1% vs those with VAF ‚â•1% (10.8 vs 8.7 months; HR = 1.40 [0.92-2.00]; p=0.12). Similarly, there was no significant difference in median rwOS (32.4 vs 23.2 months; HR 1.20 [0.74-2.00]; p=0.45). To account for potential bias due to varying effectiveness of TT by driver, we limited the analysis to pts treated with EGFR inhibitors: VAF of the EGFR mutation did not affect rwPFS (10.8 vs 9.8 months; HR 1.14 [0.69-1.90]; p=0.61) or rwOS (18.3 vs 23.2 months; HR 1.1 [0.61-2.00]; p=0.74).

Conclusions: Outcomes in pts with aNSCLC receiving matched TT after LBx were comparable between pts with driver VAF <1% and those with VAF ‚â•1%. Our findings highlight that the presence of a detectable targetable driver alt in aNSCLC is actionable, regardless of ctDNA VAF.

Alteration	VAF <1% (n = 1,185)	VAF ‚â•1% (n = 2,077)	Percentage <1% VAF [95% Confidence interval]	VAF Range
KRAS G12C	288	566	34 [31-37]	0.1% - 78%
EGFR	457	1,065	30 [28-32]	0.09% - 98%
ALK	129	126	51 [44-57]	0.04% - 49%
RET	47	32	59 [48-70]	0.04% - 36%
ROS1	41	22	65 [52-76]	0.05% - 47%
MET exon 14	75	94	44 [37-52]	0.09% - 80%
NTRK1/2/3	13	7	65 [41-84]	0.11% - 17%
BRAF V600E	71	59	55 [46-63]	0.09% - 35%
ERBB2	64	106	38 [30-45]	0.09% - 77%

Summary of Study Impact on IBTROZI:

Limited relevance. The study focuses on ctDNA VAF in aNSCLC and its association with outcomes in patients treated with targeted therapies, not specifically on ROS1-positive NSCLC or taletrectinib.

Clinical Readout:

Setting and population: Advanced NSCLC, treatment with matched targeted therapy post-liquid biopsy, ROS1 alterations included but not the primary focus, no specific CNS baseline status reported.
Efficacy signals: No significant difference in median rwPFS or rwOS between patients with driver VAF <1% and those with VAF ≥1%.
Safety/tolerability: Not reported.
Strength of evidence: Real-world data analysis, sample size of 224 for matched therapy, no control group, limitations include potential bias and lack of specific ROS1 focus.

Competitive Considerations:

This regimen does not compete directly with IBTROZI in frontline ROS1+ NSCLC or after 1 prior ROS1 TKI as it does not focus on ROS1-specific outcomes.
Does not change sequencing norms versus other ROS1 inhibitors or chemo-based options.
No specific subpopulations where IBTROZI becomes more or less attractive are identified in this study.

Clinical or Market Strategy Implications:

Medical Affairs: The study highlights the actionability of targetable driver alterations regardless of VAF, but does not provide specific insights for ROS1 or taletrectinib.
Label and evidence strategy: Does not suggest new endpoints or studies specific to ROS1 or taletrectinib.
Access and adoption: No practical advantages or burdens related to IBTROZI are discussed.

What would change your conclusion:

Missing data point #1: Specific outcomes for ROS1-positive patients treated with taletrectinib.
Missing data point #2: CNS disease status and outcomes in the ROS1-positive subset.
Decision trigger: Significant differences in durability, CNS control, or tolerability specific to ROS1-positive patients treated with taletrectinib.

Link to Abstract 8628

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Abstract Number: 8643

Comparable efficacy and safety of taletrectinib for advanced ROS1+ non–small cell lung cancer across pivotal studies and between races and world regions.

Presenter: Maurice Perol
Session: Lung Cancer—Non-Small Cell Metastatic

ABSTRACT Background: Taletrectinib is a highly potent, next-generation, central nervous system‚Äìactive, selective ROS1 tyrosine kinase inhibitor (TKI) that was evaluated in 2 pivotal ROS1+ non‚Äìsmall cell lung cancer (NSCLC) phase 2 trials: the regional TRUST-I (NCT04395677) and global TRUST-II (NCT04919811) studies. While earlier trials suggest its safety and efficacy data are consistent across racial and geographic factors, further analysis is required to confirm the consistency of outcomes and applicability of results across regions. Here, we compare the efficacy and safety of taletrectinib within and between the pivotal regional TRUST-I and global TRUST-II studies through predefined subgroup analyses.

Methods: The pivotal cohorts of TRUST-I (N=173) and TRUST-II (N=159) had similar study designs, which included the same primary endpoint (confirmed objective response rate [cORR] by independent review committee per RECIST v1.1) and secondary endpoints, as well as similar inclusion/exclusion criteria and safety evaluation methods. Key efficacy and safety profiles were compared in 3 ways: (a) between TRUST-I and TRUST-II, (b) across Western (North America and Europe) and Asian regions, and racial subgroups, in the pooled study population of TRUST-I and TRUST-II, and (c) between Western and Asian regions and other subgroups in the global TRUST-II study. Relative risk (RR) and associated 95% confidence intervals (CIs) via the Wald method were used to compare data (data cutoff June 2024).

Results: When comparing TRUST-I and TRUST-II, cORRs were consistent for TKI-naive (91% vs 85%; RR: 0.94 [95% CI: 0.83, 1.07]) and TKI-pretreated pts (52% vs 62%; RR: 1.20 [95% CI: 0.87, 1.66]). Rates of grade ‚â•3 treatment-emergent adverse events (TEAEs) were consistent across both studies (51% vs 51%, RR: 1.0 [95% CI: 0.81, 1.24]). TEAEs leading to dose interruptions (41% vs 40%) and discontinuations (6% vs 8%) were similar. In subgroup analyses of the pooled patient population by race, Asian and non-Asian patients had similar cORRs in both TKI-naive (89% vs 84%; RR: 0.94 [95% CI: 0.77, 1.15]) and TKI-pretreated (52% vs 68%; RR: 1.30 [95% CI: 0.93, 1.82]) groups. Comparison of different efficacy and safety profiles among subgroups in the pooled data set also showed consistency among races and regions. Within the multiregional TRUST-II study, cORRs were high in TKI-naive patients regardless of region (Western: 81%; Asia: 88%), prior chemotherapy (yes: 90%; no: 84%), and race (White: 83%; Asian: 86%; other: 86%). Similarly, major safety profiles were comparable between Asian and Western patients and between races within TRUST-II.

Conclusions: Taletrectinib showed comparable efficacy and safety that were not impacted by geographic and racial factors. Therefore, the clinical benefit of taletrectinib is broadly applicable to ROS1+ NSCLC patients globally.

Summary of Study Impact on IBTROZI:

Differentiation opportunity. The study reinforces taletrectinib's consistent efficacy and safety across diverse populations, highlighting its potential as a globally applicable treatment for ROS1+ NSCLC, particularly in TKI-naive and pretreated settings.

Clinical Readout:

Setting and population: Advanced ROS1+ NSCLC, both TKI-naive and post-ROS1 TKI settings; CNS baseline status not reported; prior therapies include chemotherapy.
Efficacy signals: TKI-naive ORR: 91% (TRUST-I) vs 85% (TRUST-II); TKI-pretreated ORR: 52% (TRUST-I) vs 62% (TRUST-II); consistent efficacy across racial and geographic subgroups.
Safety/tolerability: Grade 3+ TEAEs: 51% in both studies; similar rates of dose interruptions and discontinuations; consistent safety across subgroups.
Strength of evidence: Phase 2, sample sizes: TRUST-I (N=173), TRUST-II (N=159); single-arm studies; consistent efficacy and safety across regions and races.

Competitive Considerations:

This regimen competes directly with IBTROZI in both frontline ROS1+ NSCLC and post-ROS1 TKI settings, reinforcing its role in these treatment nodes.
It does not change sequencing norms but supports taletrectinib's use across diverse populations, potentially influencing global adoption.
IBTROZI remains attractive for patients with CNS disease and resistance mutations due to its consistent efficacy and safety profile.

Clinical or Market Strategy Implications:

Medical Affairs: Emphasize taletrectinib's global applicability and consistent efficacy; monitor for further subgroup analyses and real-world evidence.
Label and evidence strategy: Suggests potential for new endpoints focusing on CNS outcomes and resistance management; supports global regulatory submissions.
Access and adoption: Highlights practical advantages of consistent efficacy and safety across populations, potentially easing pathway and payer decisions.

What would change your conclusion:

Missing data point #1: Detailed CNS efficacy outcomes.
Missing data point #2: Long-term durability data beyond current follow-up.
Decision trigger: Significant differences in CNS control or durability compared to existing ROS1 inhibitors would be practice-changing.

Link to Abstract 8643

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Abstract Number: TPS8651

Phase 3 trial of the therapeutic cancer vaccine OSE2101 versus docetaxel in patients with metastatic non-small cell lung cancer and secondary resistance to immunotherapy.

Presenter: Stephen Liu
Session: Lung Cancer—Non-Small Cell Metastatic

ABSTRACT Background:

OSE2101 (TEDOPI) is a therapeutic cancer vaccine composed of multiple peptides restricted to HLA-A2 phenotype targeting tumor-associated antigens (CEA, HER-2, MAGE-2, MAGE-3, P53) frequently expressed in non-small cell lung cancer (NSCLC).

In prior studies, OSE2101 strongly induced T cell immune responses, with higher immune responses associated with longer survival (OS). In the randomized ATALANTE-1 study, OSE2101 significantly improved OS with a better safety profile and quality of life (QoL) compared to third-line chemotherapy (CT) in patients with NSCLC with progressive disease (PD) after at least 12-weeks of second line anti-PD(L)1 monotherapy.

The aim of the phase III ARTEMIA study is to confirm the benefit of OSE2101 versus CT in second-line treatment of patients with NSCLC and secondary resistance to immune checkpoint inhibitor (ICI) given in the first line setting

Methods:

HLA-A2 positive patients with metastatic NSCLC without known EGFR, ALK, ROS1 actionable gene alterations, no brain metastases, ECOG PS 0 or 1, who had PD ‚â• 24 weeks after first line CT-ICI including at least 12 weeks of maintenance ICI without cytotoxic therapy, will be randomized 2:1 to receive either OSE2101 or docetaxel.

Randomization will be stratified by histology (squamous vs non-squamous), and ECOG PS (0 or 1). Patients will receive subcutaneous OSE2101 every 3 weeks for 6 injections, then every 8 to 12 weeks up to end of year 2. In the control group, patients will receive docetaxel at 75 mg/m2 per standard of care.

Primary endpoint is OS defined as time from randomization to death of any cause. Secondary endpoints include QoL Physical, Role, and Global Health Score by EORTC QLQ-C30 questionnaire, and time to ECOG PS deterioration.

Other endpoints are safety, tumor assessments by RECIST 1.1 and Net Treatment Benefit. For patients who agree, biomarkers in tumor biopsies and blood are planned.

The primary estimand is OS in all randomized and treated patients using treatment policy approach for intercurrent events and the hazard ratio (HR) as population-level summary. Assuming a HR of 0.70 with a power of 80% using a 2-sided log-rank test, 363 patients will be enrolled to reach 269 events. An interim analysis is planned.

The ARTEMIA phase 3 study aims to confirm the benefit on survival and quality of life of the therapeutic cancer vaccine OSE2101 compared to docetaxel in second-line treatment of HLA-A2 positive patients with NSCLC and secondary resistance to immune checkpoint inhibitor. Recruitment is ongoing in North America and Europe.

Summary of Study Impact on IBTROZI:

Limited relevance. The study focuses on OSE2101, a therapeutic cancer vaccine, in a different patient population (HLA-A2 positive NSCLC without ROS1 alterations) and treatment setting (second-line post-ICI resistance), which does not directly compete with or impact IBTROZI's positioning in ROS1-positive NSCLC.

Clinical Readout:

Setting and population: Metastatic NSCLC, second-line post-ICI resistance, HLA-A2 positive, no known ROS1 alterations, no brain metastases, ECOG PS 0 or 1, North America and Europe.
Efficacy signals: Primary endpoint is OS; secondary endpoints include QoL and time to ECOG PS deterioration. Statistical assumptions include HR of 0.70, 80% power, 363 patients for 269 events. Not reported for ORR, DOR, PFS, intracranial outcomes.
Safety/tolerability: Safety assessments planned, but specific Grade 3+ AEs or discontinuation rates not reported.
Strength of evidence: Phase III, randomized 2:1, stratified by histology and ECOG PS, interim analysis planned, treatment policy approach for intercurrent events.

Competitive Considerations:

This regimen does not compete directly with IBTROZI in frontline ROS1+ NSCLC or after 1 prior ROS1 TKI, as it targets a different biomarker and patient population.
It does not change sequencing norms versus other ROS1 inhibitors or chemo-based options for ROS1+ NSCLC.
No subpopulations where IBTROZI becomes more or less attractive, as the study does not address ROS1-positive patients or CNS disease considerations.

Clinical or Market Strategy Implications:

Medical Affairs: Focus on maintaining the narrative around IBTROZI's efficacy in ROS1+ NSCLC, especially in CNS disease, and monitor developments in vaccine-based therapies for potential future relevance.
Label and evidence strategy: No immediate implications for IBTROZI; continue to emphasize CNS activity and resistance mutation coverage in ROS1+ NSCLC.
Access and adoption: No direct impact on IBTROZI's access or adoption; continue to highlight practical advantages in ROS1+ NSCLC treatment pathways.

What would change your conclusion:

Missing data point #1: Efficacy data specific to ROS1-positive NSCLC patients.
Missing data point #2: Intracranial efficacy outcomes in the context of ROS1-positive NSCLC.
Decision trigger: A significant improvement in durability, CNS control, or tolerability in a ROS1-positive NSCLC population would be practice-changing.

Link to Abstract TPS8651

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Abstract Number: TPS8652

KEYMAKER-U01 substudy 01A: Phase 1/2 study of pembrolizumab plus ifinatamab deruxtecan (I-DXd) or patritumab deruxtecan (HER3-DXd) with or without chemotherapy in untreated stage IV non–small-cell lung cancer.

Presenter: Charu Aggarwal
Session: Lung Cancer—Non-Small Cell Metastatic

ABSTRACT Background: A standard-of-care option for metastatic non‚Äìsmall-cell lung cancer (NSCLC) with no targetable genetic alterations includes pembrolizumab plus chemotherapy. However, there remains an unmet need for patients who do not respond to standard treatment. Ifinatamab deruxtecan (I-DXd) and patritumab deruxtecan (HER3-DXd) are investigational antibody-drug conjugates (ADCs) against B7 homologue 3 and human epidermal growth factor receptor 3, respectively, two proteins that are highly expressed in NSCLC tumors. Both I-DXd and HER3-DXd are conjugated with a topoisomerase 1 inhibitor payload, resulting in apoptosis of target cells. Preclinical and preliminary clinical data suggest that combining an immune checkpoint inhibitor with an ADC may provide robust antitumor activity. KEYMAKER-U01 substudy 01A (NCT04165070) is a phase 1/2, two-part, rolling arm, open-label study assessing the efficacy and safety of pembrolizumab plus an investigational agent (part A: vibostolimab, boserolimab, MK-4830, and MK-0482; part B: I-DXd and HER3-DXd), with or without chemotherapy in untreated stage IV NSCLC. We present the study design for KEYMAKER-U01 substudy 01A part B.

Methods: Eligible participants for KEYMAKER-U01 substudy 01A part B are aged ‚â•18 years with previously untreated histologically or cytologically confirmed stage IV (per American Joint Committee on Cancer v8) squamous or nonsquamous NSCLC and measurable disease per RECIST v1.1 as assessed by investigator and verified by blinded independent central review (BICR). Additional eligibility criteria include ECOG PS of 0 or 1, provision of an archival tumor sample or newly obtained biopsy of a nonirradiated tumor for biomarker analysis, and no EGFR, ALK, or ROS1 mutations for which first-line targeted therapy is indicated. In part B, 10‚Äì30 participants will be allocated to treatment arms 5‚Äì7. In Arms 5 and 6, participants will receive I-DXd plus pembrolizumab 200 mg Q3W (Arm 5) or I-DXd plus pembrolizumab with 4 cycles of carboplatin area under the curve 5 or 6 mg/ml/min (Arm 6); I-DXd dose will be at 8mg/kg. In Arm 7, participants will receive HER3-DXd 3.2, 4.8, or 5.6 mg/kg plus pembrolizumab and carboplatin. Participants can receive I-DXd and HER3-DXd until disease progression or unacceptable toxicity and pembrolizumab up to 35 cycles. The primary endpoint is incidence of dose-limiting toxicities until the start of cycle 2, and AEs and treatment discontinuations due to AEs until 40 days after last treatment (90 days for serious AEs); secondary endpoints include ORR and DOR, both per RECIST v1.1 by BICR, and pharmacokinetic parameters, including maximum concentration (C_max) and maximum trough concentration (C_trough) of I-DXd and HER3-DXd. Enrollment will be ongoing globally.

Summary of Study Impact on IBTROZI:

Limited relevance. The study focuses on investigational ADCs in combination with pembrolizumab for untreated stage IV NSCLC without targetable mutations, including ROS1, which does not directly compete with IBTROZI's current indication in ROS1-positive NSCLC.

Clinical Readout:

Setting and population: Advanced NSCLC, treatment-naive, no ROS1 mutations, stage IV, ECOG PS 0-1, no prior therapies for targetable mutations.
Efficacy signals: Not reported; primary focus on safety and dose-limiting toxicities, with secondary endpoints including ORR and DOR.
Safety/tolerability: Primary endpoint includes incidence of dose-limiting toxicities and AEs; specific Grade 3+ AEs not detailed.
Strength of evidence: Phase 1/2, small sample size (10-30 per arm), open-label, no control group, early-stage with ongoing enrollment.

Competitive Considerations:

This regimen does not compete directly with IBTROZI in frontline ROS1+ NSCLC or after 1 prior ROS1 TKI, as it targets a different patient population without ROS1 mutations.
It does not change sequencing norms versus other ROS1 inhibitors or chemo-based options for ROS1-positive patients.
No subpopulations where IBTROZI becomes more or less attractive, as the study excludes ROS1 mutations.

Clinical or Market Strategy Implications:

Medical Affairs: Focus on differentiating IBTROZI's role in ROS1-positive NSCLC; monitor for any emerging data on ADCs in ROS1-positive settings.
Label and evidence strategy: No immediate implications; continue to emphasize IBTROZI's efficacy in ROS1-positive NSCLC.
Access and adoption: No direct impact; ADCs in this study target a different NSCLC subset.

What would change your conclusion:

Missing data point #1: Efficacy outcomes specific to ROS1-positive NSCLC if explored in future studies.
Missing data point #2: CNS activity data in ROS1-positive patients.
Decision trigger: Significant efficacy or safety data in ROS1-positive NSCLC that could influence treatment sequencing or choice.

Link to Abstract TPS8652

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Abstract Number: TPS8653

ARTEMIDE-Lung03: A phase 3, randomized, double-blind, multicenter, global study of rilvegostomig or pembrolizumab in combination with platinum-based chemotherapy as first-line treatment for patients with metastatic non-squamous non-small-cell lung cancer whose tumors express PD-L1.

Presenter: Clarissa Mathias
Session: Lung Cancer—Non-Small Cell Metastatic

ABSTRACT Background:

In the United States, non-squamous histology accounts for approximately 70% of all non-small-cell lung cancers (NSCLCs), and stage IV disease with no targetable alterations is associated with poor prognosis, with a median overall survival of around 2 years. Immunotherapy targeting programmed cell death (ligand)-1 (PD-1/PD-L1) with or without platinum-based chemotherapy (PBC) is a standard of care first-line (1L) chemotherapy for patients with advanced non-squamous NSCLC. Despite the efficacy of this approach, not all patients respond to PD-1/PD-L1 immunotherapy and more effective therapeutic strategies are needed. Inhibition of the co-inhibitory T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) pathway in combination with PD-1/PD-L1 blockade to increase immunotherapy efficacy is being investigated in NSCLC, as well as other cancer types. Preliminary results (Hiltermann TJN, et al. J Thorac Oncol [WCLC] 2024; abstract OA11.03) show that rilvegostomig, a monovalent, bispecific, humanized IgG1 monoclonal antibody targeting both PD-1 and TIGIT receptors, achieved encouraging antitumor response rates and durable responses with a manageable safety profile in NSCLC. The phase 3, randomized, double-blind, multicenter ARTEMIDE-Lung03 study (NCT06627647) will assess the efficacy and safety of rilvegostomig versus pembrolizumab, in combination with platinum-based doublet chemotherapy, as 1L treatment for participants (pts) with non-squamous metastatic NSCLC (mNSCLC).

Methods:

Approximately 878 pts will be randomized 1:1 to either Arm A: rilvegostomig + PBC (pemetrexed + cisplatin or carboplatin) intravenous (IV) every three weeks (Q3W) for 4 cycles followed by rilvegostomig + pemetrexed maintenance treatment IV Q3W, or Arm B: pembrolizumab + chemotherapy IV Q3W for 4 cycles followed by pembrolizumab + pemetrexed maintenance IV Q3W. Eligibility criteria include histologically or cytologically confirmed non-squamous mNSCLC not amenable to curative treatment, tumors expressing PD-L1 (TC ‚â•1%), an Eastern Cooperative Oncology Group performance status of 0 or 1, no sensitizing EGFR mutations, ALK or ROS1 rearrangements, or mutations in other oncogenes with approved 1L therapies available. Dual primary endpoints are progression-free survival (Response Evaluation Criteria in Solid Tumors v1.1 by blinded independent central review) and overall survival. Safety/tolerability and biomarkers will also be assessed. The study will be conducted across approximately 350 sites in 25‚àí30 countries.

Summary of Study Impact on IBTROZI:

Limited relevance. The study focuses on rilvegostomig in combination with chemotherapy for PD-L1 positive non-squamous metastatic NSCLC, excluding patients with ROS1 rearrangements, thus not directly impacting IBTROZI's positioning in ROS1-positive NSCLC.

Clinical Readout:

Setting and population: Advanced non-squamous metastatic NSCLC, first-line treatment, PD-L1 expression ≥1%, excludes ROS1 rearrangements, no prior therapies for metastatic disease.
Efficacy signals: Not reported; study aims to assess PFS and OS as primary endpoints.
Safety/tolerability: Manageable safety profile reported in preliminary results; detailed safety outcomes not provided in the abstract.
Strength of evidence: Phase 3, randomized, double-blind, multicenter, 878 patients, no ROS1-positive patients included, endpoints assessed by blinded independent central review.

Competitive Considerations:

This regimen does not compete directly with IBTROZI in frontline ROS1+ NSCLC or after 1 prior ROS1 TKI, as it excludes ROS1-positive patients.
Does not change sequencing norms versus other ROS1 inhibitors or chemo-based options for ROS1-positive NSCLC.
No subpopulations where IBTROZI becomes more or less attractive, as the study excludes ROS1-positive patients.

Clinical or Market Strategy Implications:

Medical Affairs: Focus on differentiating IBTROZI's role in ROS1-positive NSCLC; monitor developments in immunotherapy combinations for broader NSCLC populations.
Label and evidence strategy: No new endpoints or studies suggested for IBTROZI based on this study; focus remains on ROS1-positive cohorts.
Access and adoption: No direct implications for IBTROZI; continue to emphasize its role in ROS1-positive NSCLC with potential CNS activity and resistance mutation coverage.

What would change your conclusion:

Inclusion of ROS1-positive patients in similar studies.
Data on efficacy of rilvegostomig in ROS1-positive NSCLC.
Significant findings on CNS control or resistance mutation management in ROS1-positive settings.

Link to Abstract TPS8653

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Abstract Number: TPS8663

A phase 1/2 open-label, multicenter, first-in-human study of the safety, tolerability, pharmacokinetics, and antitumor activity of BH-30643 in adult subjects with locally advanced or metastatic NSCLC harboring EGFR and/or HER2 mutations (SOLARA).

Presenter: Xiuning Le
Session: Lung Cancer—Non-Small Cell Metastatic

ABSTRACT Background:

Clinical outcomes for patients with metastatic EGFR-mutant NSCLC have steadily improved with successive generations of EGFR tyrosine kinase inhibitors (TKIs). However, there remains significant need for further advancement in progression-free survival (PFS) and overall survival (OS), as these outcomes still fall short when compared to the remarkable benefits observed with newer TKIs in ALK and ROS1 driven NSCLC.

BH-30643 is a first-in-class EGFR TKI with a novel macrocyclic structure offering potent, reversible, mutant selective inhibition of classical and atypical EGFR activating mutations without vulnerability to common on-target resistance mutations. Cellular activity of BH-30643 was recently described (AACR 2025) demonstrating sub-nanomolar potency for EGFR exon 19del and L858R classical mutations which are maintained in the presence of T790M +/- C797S. High potency was also observed against atypical EGFR mutations (e.g., G719X, L861Q, S768I) and exon 20 insertions, as well as mutant HER2. Such an OMNI-EGFR inhibitor may have the potential to overcome some of the limitations of earlier agents.

Methods:

SOLARA (NCT06706076, BH-30643-01) is a Phase 1/2, multicenter, open-label, dose escalation, first-in-human study to determine the safety, tolerability, pharmacokinetics, and antitumor activity of BH-30643, in adult subjects with locally advanced or metastatic NSCLC harboring EGFR and/or HER2 mutations. Enrollment based on local molecular testing and/or liquid biopsy is permitted. Asymptomatic brain metastases (treated or untreated) are eligible.

BH-30643 is administered orally twice daily until disease progression or intolerable toxicity. The study consists of an initial dose escalation part using a Bayesian optimal interval design to identify Recommended Dose(s) for Evaluation (RDE). Dose-limiting toxicities (DLTs) are evaluated for the first 21 days of treatment. A subsequent expansion part will further evaluate the RDE(s) to identify a Recommended Phase 2 Dose (RP2D), studying cohorts with or without prior systemic therapy across a range of EGFR/HER2 driver mutations. Efficacy will be evaluated by RECIST 1.1 criteria and toxicity by CTCAE V5.0. Plasma is collected for circulating tumor DNA (ctDNA) analysis at baseline and on treatment. Enrollment is underway, with planned enrollment across ~35 sites in multiple continents.

Summary of Study Impact on IBTROZI:

Limited relevance. The study focuses on BH-30643, an EGFR TKI, in EGFR-mutant NSCLC, which does not directly compete with IBTROZI's indication for ROS1-positive NSCLC.

Clinical Readout:

Setting and population: Advanced NSCLC with EGFR and/or HER2 mutations, locally advanced or metastatic, includes patients with asymptomatic brain metastases.
Efficacy signals: Not reported; study is in early phases focusing on safety and dose determination.
Safety/tolerability: Dose-limiting toxicities evaluated in the first 21 days; specific safety outcomes not yet reported.
Strength of evidence: Phase 1/2, open-label, dose escalation study; early-stage with ongoing enrollment.

Competitive Considerations:

This regimen does not compete directly with IBTROZI in frontline ROS1+ NSCLC or after 1 prior ROS1 TKI, as it targets EGFR mutations.
Does not change sequencing norms versus other ROS1 inhibitors or chemo-based options.
No direct impact on subpopulations relevant to IBTROZI, such as those with ROS1 mutations or CNS disease specific to ROS1.

Clinical or Market Strategy Implications:

Medical Affairs: Focus on differentiating IBTROZI's role in ROS1+ NSCLC; monitor for any emerging data on CNS activity or resistance mutation coverage.
Label and evidence strategy: No immediate implications; continue to emphasize IBTROZI's efficacy in ROS1+ NSCLC.
Access and adoption: No direct impact; maintain focus on IBTROZI's current positioning and monitoring requirements.

What would change your conclusion:

Missing data point #1: Efficacy outcomes specific to ROS1+ NSCLC.
Missing data point #2: Comparative CNS activity data in ROS1+ NSCLC.
Decision trigger: Significant efficacy or CNS control data in ROS1+ NSCLC that could influence practice.

Link to Abstract TPS8663

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Abstract Number: TPS8668

TACTI-004: A double-blinded, randomized phase 3 trial in patients with advanced/metastatic non-small cell lung cancer receiving eftilagimod alfa (MHC class II agonist) in combination with pembrolizumab (P) and chemotherapy (C) versus placebo + P + C.

Presenter: Giuseppe Lo Russo
Session: Lung Cancer—Non-Small Cell Metastatic

ABSTRACT Background: Eftilagimod alfa (E), an antigen presenting cell activator, binds to a subset of MHC class II molecules to mediate T cell (CD4/CD8) recruitment/activation. Prior studies in first line (1L) non-small cell lung cancer (NSCLC) (TACTI-002 [NCT03625323]: combining E + pembrolizumab (P); INSIGHT-003 [NCT03252938] combining E with chemotherapy + P [SoC]) showed encouraging efficacy results across all PD-L1 strata & excellent safety profiles. TACTI-004 is a double-blinded, randomized, placebo-controlled phase 3 study testing E + SoC vs. placebo + SoC in 1L NSCLC patients (pts).

Methods: Approximately 756 pts with 1L NSCLC will be enrolled, irrespective of PD-L1 status, & randomized 1:1 to receive either E + SoC or placebo + SoC. The dual primary endpoint (EP) is overall survival & progression-free survival (RECIST 1.1). Secondary EPs include ORR, disease control rate, duration of response, quality of life, safety & biomarkers.

Pts will receive 30 mg E SC q2w for 24 weeks, then q3w and P IV at 200 mg (30 min) q3w; both treatments for up to 2 yrs. Chemotherapy choice will be histology-dependent: non-squamous NSCLC pts will receive IV cisplatin (75 mg/m²) or carboplatin (AUC 5 or 6) + pemetrexed (500 mg/m²) q3w for 3 mo, then maintenance pemetrexed q3w. Squamous NSCLC pts will receive carboplatin (AUC 5 or 6) + paclitaxel (175 or 200 mg/m²) q3w for 3 mo. Imaging will be performed q6w until week 18, q9w until week 54 & q12w thereafter. Testing for PD-L1 (22C3) & genetic alterations will be prospectively assessed.

Key inclusion criteria: Adults diagnosed with measurable advanced/metastatic (A/M) NSCLC (squamous or non-squamous), not amenable to curative treatment nor locally available oncogenic driver mutation-based 1L therapy. Treatment-na√Øve for systemic therapy (previous palliative radiotherapy for A/M disease acceptable). Expected survival >3 months & ECOG 0 or 1. Tumour tissue must be available for PD-L1 central testing. Pts may not have tumours with EGFR mutations nor ALK or ROS1 translocations. Stable brain metastasis is acceptable.

Summary of Study Impact on IBTROZI:

Limited relevance. The study focuses on eftilagimod alfa in combination with standard of care for first-line NSCLC, excluding patients with ROS1 translocations, thus not directly impacting IBTROZI's positioning in ROS1-positive NSCLC.

Clinical Readout:

Setting and population: Advanced/metastatic NSCLC, first-line treatment, excludes ROS1 translocations, stable brain metastasis acceptable.
Efficacy signals: Primary endpoints are overall survival and progression-free survival; secondary endpoints include ORR, disease control rate, duration of response, quality of life, safety, and biomarkers. Not reported yet.
Safety/tolerability: Not reported.
Strength of evidence: Phase 3, approximately 756 patients, double-blinded, randomized, placebo-controlled, RECIST 1.1 assessment.

Competitive Considerations:

This regimen does not compete directly with IBTROZI in frontline ROS1+ NSCLC or after 1 prior ROS1 TKI, as it excludes ROS1 translocations.
It does not change sequencing norms versus other ROS1 inhibitors or chemo-based options for ROS1+ NSCLC.
No subpopulations where IBTROZI becomes more or less attractive are identified, as the study excludes ROS1 translocations.

Clinical or Market Strategy Implications:

Medical Affairs: Monitor for any indirect implications on NSCLC treatment paradigms, though direct impact on ROS1+ NSCLC is limited.
Label and evidence strategy: No new endpoints or studies suggested for IBTROZI based on this study.
Access and adoption: No practical advantages or pathway implications for IBTROZI inferred from this study.

What would change your conclusion:

Missing data point #1: Efficacy outcomes specific to ROS1+ populations.
Missing data point #2: Safety and tolerability data relevant to ROS1+ NSCLC.
Decision trigger: Significant efficacy or safety data in ROS1+ populations that could influence treatment sequencing or choice.

Link to Abstract TPS8668

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Abstract Number: 10050

Updated efficacy and safety of entrectinib in children with extracranial solid or primary central nervous system (CNS) tumors harboring ROS1 fusions.

Presenter: Ami Desai
Session: Pediatric Oncology

ABSTRACT Background: Entrectinib is a TRK and ROS1 inhibitor that has shown rapid and durable responses in children with NTRK1/2/3 or ROS1 fusion-positive (fp) extracranial solid or primary CNS tumors in an integrated analysis of the STARTRK-NG (NCT02650401), TAPISTRY (NCT04589845) and STARTRK-2 (NCT02568267) trials. These data led to FDA and EMA approval of entrectinib in pediatric patients >1 month with NTRK fp tumors. Here we present updated data on pediatric patients with ROS1 fp tumors based on the trials listed above to further describe the efficacy and safety of entrectinib in this population.

Methods: Eligible pts were TRK/ROS1 inhibitor-na√Øve, <18 years old, with locally advanced/metastatic extracranial solid or primary CNS tumors, with measurable or evaluable-only disease. All pts who received ‚â•1 daily dose of oral entrectinib are included in the safety-evaluable population. Pts who had a ROS1 fusion and were followed for ‚â•6 months are included in the ROS1 efficacy-evaluable population. Pts received entrectinib until disease progression, unacceptable toxicity, or consent withdrawal. Tumor responses were confirmed by blinded independent central review (BICR) per RECIST v1.1 or RANO criteria. Primary endpoint: confirmed objective response rate (ORR) per BICR. Key secondary endpoints: ORR in pts with baseline measurable disease per BICR; duration of confirmed response (DoR); time to confirmed response (TTR); clinical benefit rate (CBR); progression-free survival (PFS); overall survival (OS); safety.

Results: At clinical cut-off (16 July 2024), of the 113 safety-evaluable pts, there were 26 pts in the ROS1 efficacy-evaluable cohort. ORR was 69.2% (95% CI 48.2, 85.7). Median TTR was 1.84 months. Median OS was not evaluable. Median duration of survival follow-up was 29.4 months (range 1‚Äì80). Efficacy outcomes are shown in the table. The most common related adverse events were weight gain (37.2%), anemia (36.3%), and AST increase (26.5%). Related fracture events occurred in 23% of pts.

Conclusions: Entrectinib yielded rapid and durable responses in pediatric pts with ROS1 fp extracranial solid or primary CNS tumors. The safety profile of entrectinib was consistent with previous reports.

Efficacy	*ROS1* (N=26)
*Confirmed ORR, N, % [95% CI]**	18, 69.2 [48.2- 85.7]
Complete response	4, 15.4 [4.4- 34.9]
Partial response	14, 53.8 [33.4- 73.4]
*Median confirmed DoR, months (95% CI)**	NE (16.2- NE)
*Median TTR, months (range)**	1.84 (1.6- 4.0)
*CBR, % (95% CI)**	84.6 (65.1- 95.6)
*Median PFS, months (95% CI)**	NE (21.8- NE)
Median OS, months (95% CI)	NE (NE- NE)

*Per BICR; CI, confidence interval; NE, not evaluable.

Summary of Study Impact on IBTROZI:

Limited relevance. The study focuses on pediatric patients with ROS1 fusion-positive extracranial solid or primary CNS tumors, which is outside the adult advanced ROS1-positive NSCLC setting where IBTROZI is indicated.

Clinical Readout:

Setting and population: Pediatric patients with locally advanced/metastatic extracranial solid or primary CNS tumors, TRK/ROS1 inhibitor-naïve, ROS1 fusion-positive, no specific CNS baseline status reported.
Efficacy signals: ORR 69.2% (95% CI 48.2, 85.7), median TTR 1.84 months, median PFS and OS not evaluable.
Safety/tolerability: Common AEs included weight gain (37.2%), anemia (36.3%), AST increase (26.5%), and fractures (23%).
Strength of evidence: Integrated analysis from multiple trials, 26 ROS1 efficacy-evaluable patients, BICR assessment, pediatric focus.

Competitive Considerations:

This regimen does not compete directly with IBTROZI in the adult ROS1+ NSCLC setting.
Does not change sequencing norms versus other ROS1 inhibitors or chemo-based options in adult NSCLC.
No direct implications for IBTROZI's attractiveness in subpopulations like CNS disease or resistance mutations in adult NSCLC.

Clinical or Market Strategy Implications:

Medical Affairs: Focus on maintaining the narrative around IBTROZI's adult NSCLC efficacy and safety profile; monitor pediatric ROS1 developments for potential future implications.
Label and evidence strategy: No immediate changes suggested; continue focusing on adult NSCLC endpoints and resistance management.
Access and adoption: No direct impact on current pathways or payer strategies for adult NSCLC.

What would change your conclusion:

Missing data point #1: Adult ROS1+ NSCLC efficacy data for entrectinib.
Missing data point #2: CNS-specific outcomes in adult populations.
Decision trigger: Significant differences in durability, CNS control, or tolerability in adult NSCLC populations.

Link to Abstract 10050

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Abstract Number: e15073

Micro-mosaicism of BRAF V600E oncogene in normal skin samples of patients with Erdheim-Chester disease.

Presenter: Julien Haroche
Session: Publication Only: Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology

ABSTRACT Background:

Erdheim-Chester disease (ECD) is a histiocyte neoplasm with frequent long bone, retroperitoneal, cardiovascular and/or central nervous system (CNS) involvements. More than half of ECD patients harbor a BRAF^V600E mutation, and treatment with BRAF and/or MEK inhibitors is highly efficient in most patients. BRAF^V600E is also frequent in Langerhans cell histiocytosis (LCH), which co-occurs in 14% of patients with ECD. Both ECD and LCH are associated with neurodegeneration (ND) predominating in cerebellum and pons. Detection of BRAF V600E was recently reported in microglia of brain samples of 8 patients with ECD or LCH, some of whom did not have ND (Vicario 2024). In mice, both microglia and epidermal Langerhans cells are self-renewed cells derived from yolk-sac progenitors.

Methods:

Patients with Erdheim-Chester with BRAF^V600E mutation were included in this study. Normal skin samples were obtained either from biopsies in clinically healthy areas or from margin of basal cell carcinoma. Histology analysis of all samples excluded any histiocytosis or melanocytic tumor infiltration. Rolls were analyzed using digital PCR for wild type and V600E variants of BRAF as described (H√©lias‚ÄêRodzewicz 2023). Samples were considered as negative for BRAF^V600E, when sequencing depth of BRAF was >10,000 (biopsies) or >20,000 (blood or bone marrow (BM) cells.

Results:

Twenty patients were included with median age 68 years (11males/9females). Nine patients were treated with BRAF and/or MEK inhibitors at time of skin biopsy. Eight patients had ND, and 5 had clonal hematopoiesis. BRAF^V600E was detected in 18/20 patients. The variant allele frequency (VAF) was always <1% (median 0.16%, range 0.01% to 0.69%). Median VAF in normal skin was significantly lower than in histiocytosis infiltrated tissues (0.16% (IQR 0.06-0.19) vs 4.3% (IQR 2.9-13), p<0001). Two of the patients had 2 distinct skin biopsies, both positive for BRAF^V600E. Blood and/or bone marrow cells were analyzed in 11 patients with BRAF^V600E positive normal skin: 6 contained BRAF^V600E, while 5 were wild type. ND was observed in 4/5 patients skin-positive and blood-negative for BRAF^V600E, but in only 2/6 skin-positive and blood-negative for BRAF^V600.

Conclusions:

The oncogenic BRAF^V600E variant is frequently present in normal skin of patients with ECD, even during treatment with BRAF/MEK inhibitors. The VAF is lower than in histiocytosis infiltrated biopsies. This suggest that these patients may have a micro-mosaicism of BRAF^V600E within self-renewing epidermal Langerhans cells.

Summary of Study Impact on IBTROZI:

Limited relevance. The study focuses on Erdheim-Chester disease and the presence of the BRAF^V600E mutation, which is not directly related to ROS1-positive NSCLC or the clinical positioning of IBTROZI (taletrectinib).

Clinical Readout:

Setting and population: Erdheim-Chester disease patients with BRAF^V600E mutation; not applicable to ROS1-positive NSCLC.
Efficacy signals: Not reported; study focuses on detection of BRAF^V600E in normal skin and its implications.
Safety/tolerability: Not reported; study does not address safety or tolerability in the context of ROS1 inhibitors.
Strength of evidence: Small sample size (20 patients), observational study, no control group, focused on genetic analysis rather than therapeutic outcomes.

Competitive Considerations:

This regimen does not compete directly with IBTROZI in frontline ROS1+ NSCLC or after 1 prior ROS1 TKI.
Does not change sequencing norms versus other ROS1 inhibitors or chemo-based options.
No subpopulations where IBTROZI becomes more or less attractive based on this study.

Clinical or Market Strategy Implications:

Medical Affairs: No direct implications for IBTROZI; focus remains on ROS1+ NSCLC.
Label and evidence strategy: No new endpoints or studies suggested for IBTROZI based on this study.
Access and adoption: No impact on practical advantages or pathway implications for IBTROZI.

What would change your conclusion:

Missing data point #1: Direct evidence of efficacy or safety in ROS1-positive NSCLC.
Missing data point #2: Comparative analysis with ROS1 inhibitors in a relevant population.
Decision trigger: Significant findings in ROS1-positive NSCLC regarding durability, CNS control, or tolerability.

Link to Abstract e15073

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Abstract Number: e20015

Racial disparities in molecularly targeted trials of tyrosine kinase inhibitors (TKI) for the perioperative management of oncogene-driven non-small cell lung cancer (NSCLC): A systematic review.

Presenter: Oluwamuyiwa Adebayo
Session: Publication Only: Lung Cancer—Non–Small Cell Local-Regional/Small Cell/Other Thoracic Cancers

ABSTRACT Background:

The treatment of non-small cell lung cancer (NSCLC) has experienced a significant shift with the introduction of targeted therapies. While the utility of targeted therapies for the perioperative management of oncogene-driven NSCLC is rapidly evolving through molecularly targeted trials, racial disparities of patient (pt) enrollment in these trials remains uncharacterized.

Methods:

A systematic review of 27 clinical trials from ClinicalTrials.gov, conducted between 2003 and 2024, was performed to evaluate targeted therapies in resectable NSCLC. Data on genomic alterations, outcomes, demographics, drugs, trial phases, racial distribution and geographic representation were collected.

Results:

Most studies, 67% (18/27) evaluated therapies targeting EGFR mutations, followed by ALK (26%), ROS1 (14.8%), MET (7.4%), KRAS (7.4%), BRAF (3.7%), and RET (3.7%). Out of 27 studies, 18.5% (5/27) were completed, 18.5% (5/27) were recruiting, 29.6% (8/27) were active but not recruiting, 22.2% (6/27) were not yet recruiting, 3.7% (1/27) was terminated, and 7.4% (2/27) had an unknown status. Most (70.3%) trials were phase II, with a primary endpoint of Objective Response Rate (ORR). Sample size data were only reported in seven (25.9%) studies, with a cumulative reported enrollment of 993 participants. Women accounted for 64.9% of participants, while men represented 34.5%. Racial distribution reported by a few studies was 14.8% (4/27) with a sample size of 969 and revealed underrepresentation of Black (0.1%), Hispanic (0.2%), and other racial groups (1.2%), while White and Asian participants constituted 37.8% and 60.7%, respectively. Studies were predominantly conducted in China (59.2%,16/27) and the United States (44.4% 12/27).

Conclusions:

Targeted therapies continue to transform the management of resectable oncogene-driven NSCLC, offering significant potential to improve outcomes in this subset of patients. However, disparities in racial representation and geographic distribution persist, underscoring the need for more inclusive and globally representative research. Future studies should address these disparities, explore resistance mechanisms, and optimize therapy combinations to broaden the impact of targeted therapies in diverse patient populations.

Summary of Study Impact on IBTROZI:

Limited relevance. The abstract focuses on racial disparities in clinical trials for resectable NSCLC, with a minor emphasis on ROS1-targeted therapies. It does not provide direct efficacy or safety data relevant to IBTROZI's positioning in advanced ROS1-positive NSCLC.

Clinical Readout:

Setting and population: Resectable NSCLC, various oncogene targets including ROS1, no specific CNS baseline status or prior therapies reported.
Efficacy signals: Not reported.
Safety/tolerability: Not reported.
Strength of evidence: Systematic review of 27 trials, predominantly phase II, with limited sample size reporting and racial distribution data.

Competitive Considerations:

This regimen does not compete directly with IBTROZI in frontline ROS1+ NSCLC or after 1 prior ROS1 TKI.
Does not change sequencing norms versus other ROS1 inhibitors or chemo-based options.
No subpopulations where IBTROZI becomes more or less attractive are identified.

Clinical or Market Strategy Implications:

Medical Affairs: Highlights the need for more inclusive trial designs; no direct impact on IBTROZI's scientific narrative.
Label and evidence strategy: Suggests a need for more diverse patient representation in future studies, but no new endpoints or cohorts directly relevant to IBTROZI.
Access and adoption: No practical advantages or burdens identified; no pathway or payer implications.

What would change your conclusion:

Missing data point #1: Specific efficacy and safety outcomes for ROS1-targeted therapies in advanced NSCLC.
Missing data point #2: CNS disease status and outcomes in the context of ROS1-targeted therapies.
Decision trigger: Significant efficacy or safety data specific to ROS1-positive advanced NSCLC that could influence practice.

Link to Abstract e20015

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Abstract Number: e20044

Neoadjuvant and adjuvant iruplinalkib in resectable ALK or ROS1 fusion-positive, non-small cell lung cancer (NSCLC): The preliminary results of the single-arm, exploratory Neo-INFINITY study.

Presenter: Guodong Zhang
Session: Publication Only: Lung Cancer—Non–Small Cell Local-Regional/Small Cell/Other Thoracic Cancers

ABSTRACT Background: The ALNEO, NAUTIKA1, and SAKULA studies found perioperative alectinib and ceritinib were effective for resectable ALK-positive NSCLC. The Neo-INFINITY study aimed to evaluate the efficacy and safety of perioperative iruplinalkib for resectable ALK- or ROS1-positive NSCLC. Here, the preliminary results of Stage 1 were reported.

Methods: This single-arm phase II trial was conducted in China. Adult patients with pathologically confirmed resectable ALK- or ROS1-positive NSCLC at stage IB‚ÄìIIIA or IIIB (T3N2M0 only), ‚â•one measurable lesion via RECIST v1.1, ECOG performance status of 0 or 1 were eligible. Patients received neoadjuvant iruplinalkib orally at 180 mg/day (with a 7-day lead-in at 60 mg/day) for eight weeks, followed by surgery and then adjuvant iruplinalkib (the same dose and lead-in). The total treatment period was up to two years. The primary endpoint was major pathologic response (MPR). Simon's optimal two-stage design was implemented. The study would be stopped early if ‚â§one of eight patients achieving MPR at Stage 1. Another 18 patients would be enrolled at Stage 2.

Results: From Feb 2023 to Jun 2024, 10 patients were enrolled. Two are still on neoadjuvant treatment, and eight patients who completed neoadjuvant treatment and surgery were included for analysis. Median age was 59 years (range 35‚Äì78). Two (25%) were male. One (12%) had squamous cell carcinoma, and ALK fusions were found in six (75%) patients. MPR and pathologic complete response (pCR) were achieved in four (50%) and two (25%) of eight patients, respectively. Among six ALK-positive cases, four (67%) patients obtained MPR, and two (33%) reached pCR. Objective response was observed in all eight (100%) patients. Radiologic downstaging was found in four (50%) patients. All patients underwent R0 resection. During iruplinalkib treatment, ‚â•grade 3 iruplinalkib-related adverse events (AE) were reported in two (25%) patients, the most common of which were alanine aminotransferase increased (two [25%]) and aspartate aminotransferase increased (one [12%]). Serious AE, iruplinalkib-related AE leading to dose interruption, reduction, and discontinuation occurred in zero, one (12%), one (12%), and zero patient, respectively.

Conclusions: Neoadjuvant iruplinalkib is effective and feasible for resectable ALK- or ROS1-positive NSCLC, with acceptable safety profiles. Stage 2 of the study is ongoing, and long-term results are awaited.

Efficacy endpoints.

Endpoints	All patients (n=8)	ALK-positive patients (n=6)
Major pathologic response	4 (50%)	4 (67%)
Pathologic complete response	2 (25%)	2 (33%)
Objective response	8 (100%)	6 (100%)
Radiologic downstaging	4 (50%)	2 (33%)
R0 resection	8 (100%)	6 (100%)

Note: Data are presented as n (%).

Summary of Study Impact on IBTROZI:

Limited relevance. The study focuses on neoadjuvant iruplinalkib for resectable ALK- or ROS1-positive NSCLC, which is outside the advanced setting where IBTROZI is indicated. Bridging evidence would be needed to establish relevance to IBTROZI's current positioning in advanced ROS1-positive NSCLC.

Clinical Readout:

Setting and population: Resectable ALK- or ROS1-positive NSCLC, stage IB-IIIA or IIIB (T3N2M0 only), neoadjuvant setting, no specific CNS baseline status reported, prior therapies not applicable.
Efficacy signals: MPR 50%, pCR 25%, ORR 100%, radiologic downstaging 50%, R0 resection 100%; no intracranial outcomes reported.
Safety/tolerability: Grade 3+ AEs in 25% of patients, including increased alanine and aspartate aminotransferase; dose interruption and reduction in 12% of patients.
Strength of evidence: Phase II, single-arm, small sample size (n=8 analyzed), no control group, early-stage results, RECIST v1.1 assessment method.

Competitive Considerations:

This regimen does not compete directly with IBTROZI in frontline ROS1+ NSCLC or after 1 prior ROS1 TKI, as it is focused on a resectable, neoadjuvant setting.
It does not change sequencing norms versus other ROS1 inhibitors or chemo-based options in the advanced setting.
No subpopulations identified where IBTROZI becomes more or less attractive based on this study.

Clinical or Market Strategy Implications:

Medical Affairs: The study highlights the potential of neoadjuvant therapy in resectable NSCLC, but does not impact IBTROZI's current strategic narrative in advanced disease. Monitor for long-term results and any shifts in neoadjuvant treatment paradigms.
Label and evidence strategy: No immediate implications for IBTROZI's label or evidence strategy, as the study does not address advanced disease endpoints or resistance management.
Access and adoption: No practical advantages or burdens identified that would affect IBTROZI's access or adoption in its current indication.

What would change your conclusion:

Missing data point #1: Efficacy and safety data in an advanced ROS1-positive NSCLC population.
Missing data point #2: Intracranial efficacy outcomes relevant to CNS disease management.
Decision trigger: A significant difference in durability, CNS control, or tolerability in an advanced setting that aligns with IBTROZI's current indication would be practice-changing.

Link to Abstract e20044

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Abstract Number: e20659

Real-life efficacy and safety data of lorlatinib treatment in ROS-1–positive advanced non-small cell lung cancer: Turkish Oncology Group (TOG) study.

Presenter: Sedat Biter
Session: Publication Only: Lung Cancer—Non-Small Cell Metastatic

ABSTRACT Background:

ROS-1-positive non-small cell lung cancers (NSCLCs) are rare, accounting for approximately 1-2% of all NSCLCs. Lorlatinib is a potent, third-generation tyrosine kinase inhibitor targeting ALK and ROS1 with preclinical activity against most of the known resistance mutations in ALK and ROS1, with good cranial efficacy. Lorlatinib has shown clinical activity in patients with advanced ROS1-positive NSCLC, including those with CNS metastases and those previously treated with crizotinib, in phase 1 to 2 clinical trials. We aimed to present real-life data on the efficacy and safety of lorlatinib in ROS-1 positive NSCLC patients.

Methods:

Our study is a retrospective study and ROS-1 positive patients with NGS or FISH techniques among non-small cell lung cancer patients between 2014 and 2024 were included in the study. A total of 52 patients from twenty oncology centers were eligible for the study. Median progression-free survival (mPFS) and overall survival (mOS) were estimated by analyzing the Kaplan-Meier curve.

Results:

Median age of patients was 52 years. 33 (63.5%) of our patients were male, and 23 (44%) had never smoked. 49 (94%) patients had adenocarcinoma histology. At the time of diagnosis, 48 (92%) of the patients were metastatic and 12 (23%) had brain metastases. In first-line 39 (75%) patients received crizotinib and in second-line 41 (78%) patients were treated with lorlatinib. At least 3 or more metastatic sites were present in 37 (71%) patients before lorlatinib treatment. Median follow-up was 20.4 months and mPFS with lorlatinib treatment was 27.2 months. Side effects were observed in 38 (73%) patients with lorlatinib, and 10 (19%) had grade 3-4-5 side effects. The most common grade 3-4 side effect was hyperlipidemia, which was seen in 4 (7.7) of the patients. Dose reduction was performed in 10 (19%) patients due to side effects and treatment was interrupted in 8 (15%) of them. Treatment was not discontinued in any patient due to side effects.

Conclusions:

In summary, lorlatinib showed clinical activity in patients with advanced ROS1-positive NSCLC. Lorlatinib has side effects and these side effects are manageable. There are few treatment options for patients who progress under crizotinib therapy, lorlatinib can be used safely and effectively as a next-line targeted agent. Research Sponsor: None.

Summary of Study Impact on IBTROZI:

Competitive threat. The study highlights lorlatinib's efficacy in ROS1-positive NSCLC, particularly post-crizotinib, which may challenge IBTROZI's positioning in the post-ROS1 TKI setting.

Clinical Readout:

Setting and population: Advanced NSCLC, post-crizotinib treatment, ROS1-positive defined by NGS or FISH, 23% with baseline brain metastases.
Efficacy signals: Median PFS of 27.2 months with lorlatinib; intracranial outcomes not specifically reported.
Safety/tolerability: 73% experienced side effects, 19% had grade 3-4-5 AEs, primarily hyperlipidemia; dose reductions in 19%.
Strength of evidence: Retrospective study, 52 patients, no control group, limited by retrospective design and potential selection bias.

Competitive Considerations:

This regimen competes directly with IBTROZI in the post-ROS1 TKI setting, particularly after crizotinib.
It may influence sequencing norms by positioning lorlatinib as a viable option post-crizotinib, potentially affecting IBTROZI's use in this node.
IBTROZI may be less attractive in patients with CNS disease due to lorlatinib's known cranial efficacy, though specific intracranial data was not reported in this study.

Clinical or Market Strategy Implications:

Medical Affairs: Emphasize IBTROZI's resistance mutation coverage and CNS activity; monitor lorlatinib's adoption and real-world outcomes.
Label and evidence strategy: Consider studies focusing on resistance mutations and CNS outcomes to differentiate IBTROZI.
Access and adoption: Highlight IBTROZI's safety profile and monitoring simplicity compared to lorlatinib's hyperlipidemia management.

What would change your conclusion:

Missing data point #1: Specific intracranial efficacy data for lorlatinib.
Missing data point #2: Direct comparison of lorlatinib and IBTROZI in a head-to-head study.
Decision trigger: A significant difference in CNS control or a more favorable safety profile for IBTROZI could shift practice patterns.

Link to Abstract e20659

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Abstract Number: e20685

Real-world data on the treatment of patients with ROS1-positive non-small cell lung cancer.

Presenter: Daniil Stroyakovskiy
Session: Publication Only: Lung Cancer—Non-Small Cell Metastatic

ABSTRACT Background: ROS1 rearrangements, present in 1‚Äì2% of non-small cell lung cancer (NSCLC) cases, are targetable by ALK inhibitors due to the structural similarities between ROS1 and ALK. This study evaluates the real-world effectiveness of ALK inhibitors in treating patients with ROS1-positive NSCLC

Methods: We conducted a retrospective analysis of patients diagnosed with ROS1-positive NSCLC and treated with ALK inhibitors in Moscow from 2019 to 2024. Data on progression-free survival (PFS), overall survival (OS), treatment response, clinicopathologic characteristics, and factors influencing outcomes were collected. Survival outcomes were analyzed using Kaplan-Meier curves, with Log Rank tests and Cox regression used for statistical comparisons and hazard ratio (HR) calculations.

Results: The study included 107 patients: 61.7% female and 75% never-smokers. A high proportion (78.1%) had metastatic disease at diagnosis, with lungs (54.7%), bones (29.2%), and brain (21.7%) as common metastatic sites. Crizotinib was the predominant ALK inhibitor used, administered as first-line therapy in 70.8% of cases. At a median follow-up of 31 months, the median OS was 56 months, with a 5-year OS rate of 36% (95% CI: 27.9‚Äì45.2). Median PFS was 15 months (95% CI: 4.8‚Äì25.2), with a 5-year PFS rate of 23% (95% CI: 16.3‚Äì30.2). Therapy response rates included complete response (5.0%), partial response (26.7%), stable disease (57.4%), and progressive disease (10.9%). No significant survival differences were observed between PD-L1-positive and PD-L1-negative patients.

Conclusions: This study represents the most extensive real-world analysis from Russia on the treatment of ROS1-positive NSCLC with ALK inhibitors, particularly crizotinib. It confirms favorable progression-free survival (PFS) and overall survival (OS) outcomes comparable to those observed in registration trials. The results reinforce the crucial role of genomic profiling in NSCLC for personalized treatment approaches. Further research is recommended to enhance outcomes for patients with brain metastases or suboptimal initial responses to therapy.

Summary of Study Impact on IBTROZI:

Limited relevance. The study focuses on ALK inhibitors in ROS1-positive NSCLC, primarily crizotinib, and does not directly address taletrectinib or its specific clinical positioning.

Clinical Readout:

Setting and population: Advanced NSCLC, predominantly metastatic; ROS1-positive defined; 21.7% with brain metastases; first-line crizotinib use in 70.8% of cases.
Efficacy signals: Median OS of 56 months, median PFS of 15 months; response rates: CR 5.0%, PR 26.7%, SD 57.4%, PD 10.9%.
Safety/tolerability: Not reported.
Strength of evidence: Retrospective analysis, 107 patients, single-arm, real-world setting, limitations in generalizability.

Competitive Considerations:

This regimen does not compete directly with IBTROZI in frontline ROS1+ NSCLC or after 1 prior ROS1 TKI, as it focuses on ALK inhibitors.
Does not change sequencing norms versus other ROS1 inhibitors or chemo-based options.
No specific subpopulations where IBTROZI becomes more or less attractive are identified.

Clinical or Market Strategy Implications:

Medical Affairs: Highlights the importance of genomic profiling; no direct implications for taletrectinib.
Label and evidence strategy: Suggests a need for further research on brain metastases and initial response optimization, but not directly related to taletrectinib.
Access and adoption: No practical advantages or burdens identified for taletrectinib from this study.

What would change your conclusion:

Missing data point #1: Direct comparison of taletrectinib with ALK inhibitors in ROS1-positive NSCLC.
Missing data point #2: Specific intracranial efficacy data for taletrectinib.
Decision trigger: Significant differences in CNS control or durability compared to current ROS1 inhibitors would be practice-changing.

Link to Abstract e20685