2025 World Conference on Lung Cancer: The 10 Most Notable Studies

Innovations in Lung Cancer Treatment – 2025

Lung cancer treatment is undergoing a marked evolution from single-agent approaches toward rational combination strategies . Studies presented at IASLC 2025 show that targeted therapy + chemotherapy synergy has become established, ADCs are having an increasing impact, perioperative immunotherapy is becoming a standard in early-stage disease, and CNS control is a focus for new TKIs. Some negative results (e.g., adjuvant crizotinib) are making clinical practice more evidence-based and selective .

In 2025, lung cancer treatment is advancing toward personalization by molecular phenotype, CNS targeting and combination-focused approaches . Clinical decisions will increasingly be guided by patient preferences, comorbidities, access/reimbursement and real-world data, along with dynamic biomarkers such as ctDNA (MRD) .

Study 1 — Iza-bren (izalontamab brengitecan) + Osimertinib

Why does it matter? Achieving a strong, durable first-line response remains one of the most critical needs in EGFR-mutant NSCLC. Combining the antibody-drug conjugate (ADC) iza-bren with osimertinib has attracted attention in early-phase data through exceptionally high response rates and 12-month survival rates. This is one of the few examples demonstrating the clinical potential of TKI + ADC synergy in targeted treatment.

📊 Quick Summary (Key Numbers)

• ORR: %100 (confirmed ORR %95) — 2.5 mg/kg, D1D8, Q3W dose cohort
• 12-month PFS rate: %92.1 (median PFS: —)
• 12-month OS rate: %94.8 (median OS: —)
• Tolerability: Manageable safety profile; hematologic AEs most common; low interruption rate

Note: Follow-up ~12–13 months; early-phase data—interpretations are specific to the dose cohort.

🧱 Study Design and Population

• Phase: Phase 2 (NCT05880706)
• Population: EGFR-mutant, locally advanced / metastatic NSCLC
• Regimen: Iza-bren 2.5 mg/kg D1 & D8, Q3W + osimertinib (standard dose)
• Follow-up: Median for PFS ≈ 12.5 months; median for OS ≈ 12.8 months
• Sample size: Limited reporting in the presentation—results focused on the dose cohort

📈 Results in Numbers

🧯 Safety and Tolerability

• The most commonly reported adverse events were hematologic (limited details of grades and rates were shared).
• Rates of dose interruption/discontinuation were low; the overall profile was manageable .
• No new safety signal was reported with combined osimertinib use.

🧭 What Do These Results Mean?

ADC + TKI may prolong the duration of response achievable with TKI monotherapy and reduce early progression . With an ORR of up to 100% and, at 12 months, PFS exceeding 92% , this PFS rate points to a first-line approach for patients with high tumor burden and/or a risk of brain metastasis that is biologically attractive. However, translation into routine clinical practice still requires comparative phase 3 evidence.

🚧 Limitations (Points to Consider)

• Early-phase / dose-cohort data—limited generalizability to a broad population.
• No comparator arm (single arm) → cautious interpretation of effect size is necessary.
• Follow-up ~12–13 months; long-term OS/DOR are not yet mature.
• Sample size and subgroup details in the presentation were limited .

🚀 Place in Clinical Practice and Future Outlook

• For now, use is recommended in a clinical trial setting; phase 3 evidence is awaited before routine adoption.
• Ongoing phase 3 study: NCT06838273 (China)—results will determine whether the combination can become a first-line standard .
• Future analyses specifically addressing brain metastasis subgroups and resistance biology (e.g., EGFR C797S, MET amplification) will be critical.

Editor's note: This content is based on IASLC 2025 conference presentation data; figures are specific to the reported dose cohort.

Study 2 — FLAURA2: Osimertinib + Chemotherapy (1st Line)

Why does it matter? In advanced EGFR-mutant NSCLC, osimertinib monotherapy has long been a first-line standard. FLAURA2updated data confirm that osimertinib + platinum/pemetrexed significantly improves not only PFS but also overall survival (OS) to a clinically meaningful extent. This is reshaping first-choice algorithms in many centers.

📊 Quick Summary (Key Numbers)

• Median OS: Combination 47.5 months versus monotherapy 37.6 months → 23% reduction in the risk of death
• PFS (previously reported): %38 reduction in the risk of progression/death
• Safety: Manageable; with additional follow-up, no new signal

Note: OS follow-up ~51.2 months; results are statistically significant and clinically valuable.

🧱 Study Design and Intervention

• Phase: Phase 3 (NCT04035486)
• Population: EGFR-mutant (usually exon 19 deletion / L858R) advanced NSCLC
• Arms:
  • Combination: Osimertinib + platinum/pemetrexed induction → osimertinib + pemetrexed maintenance
  • Control: Osimertinib monotherapy
• Primary/secondary endpoints: PFS, OS, response rates, safety

📈 FLAURA2 in Numbers

🧭 What Changes in Practice?

• First-line combination therapyis being adopted by many centers as a new SOC .
• High tumor burden, risk of early progression or a high probability of brain metastasis provide reasons for a more aggressive initial approach in patients at high risk.
• In real-world practice, chemotherapy eligibility (hematologic reserve, comorbidities) and patient preference are important determinants.

👥 Selecting the Patient Profile—When to Use a Combination?

• Performance status good (ECOG 0–1)
• High tumor burden / need for rapid control
• Risk of brain metastasis high-risk cases
• Hematologic reserve adequate, low comorbidity burden
• Patient preference: willing to accept greater intensity for potentially longer OS

Alternative: Monotherapy remains reasonable for patients with substantial comorbidities who cannot tolerate chemotherapy.

🧯 Safety and Management Tips

• Hematologic toxicity: for neutropenia/anemia, dose delays, G-CSF and supportive care
• Renal function & folate/B12 monitoring: prerequisites for pemetrexed
• Monitoring frequency: closer during the first 3–4 months (blood counts, symptom screening)

🚧 Limitations and Open Questions

• Cost and access: Economic burden of the combination / reimbursement conditions
• Older and frail populations need real-world data
• Resistance patterns: Molecular resistance profiles after combination therapy and 2L options

📝 Final Thoughts

FLAURA2clearly demonstrated the first-line osimertinib + chemotherapy combination's OS advantage in EGFRm NSCLC. Its impact on clinical practice is clear: the combination is increasingly becoming the default choice for eligible patients.

Study 3 — CheckMate 77T: Perioperative Nivolumab (Resectable NSCLC)

Why does it matter? Recurrence risk is high in early-stage, surgically treatable NSCLC, and preoperative/postoperative (perioperative) strategies determine long-term outcomes. Neoadjuvant nivolumab + platinum-doublet chemotherapy followed after surgery by adjuvant nivolumab was evaluated in CheckMate 77T, which not only prolonged event-free survival (EFS) but also increased pathological complete response (pCR) rates without adversely affecting health-related quality of life (HRQOL) .

📊 Quick Summary (Key Numbers)

• EFS (median): In the nivolumab arm, not reached versus placebo 18.4 months
• pCR: Increased with nivolumab (neoadjuvant immunotherapy + chemotherapy synergy)
• HRQOL: Reduced risk of deterioration; particularly stage III N2 cases showed clear benefit
• Safety: Generally manageable, consistent with expected class effects

Note: Patients with EGFR mutations or ALK rearrangements were excluded; the population comprised adults with resectable NSCLC.

🧱 Study Design and Intervention

• Phase: Phase 3 (NCT04025879)
• Population: Resectable stage III N2 or non-N2 NSCLC (EGFR/ALK negative)
• Arms:
  • Experimental: Neoadjuvant nivolumab + platinum-doublet chemotherapy → surgery → adjuvant nivolumab
  • Control: Neoadjuvant placebo + platinum-doublet chemotherapy → surgery → adjuvant placebo
• Main endpoints: EFS, pCR/MPR, HRQOL (time to definitive deterioration, TTDD), safety

📈 CheckMate 77T in Numbers

🧭 What Do the HRQOL Findings Mean?

The finding that chemotherapy added to neoadjuvant immunotherapy and postoperative adjuvant nivolumab did not substantially impair quality of lifeshows that perioperative IO strategies are sustainable in terms of oncological outcomes as well as patient-reported outcomes . In particular, in stage III N2 cases, the longer time to deterioration (delayed TTDD) is valuable in clinical practice.

🧯 Safety: Practical Tips

• Immune-related AEs: for dermatitis, thyroiditis, hepatitis, and pneumonitis, early diagnosis and algorithm-based management
• Perioperative timing: Observe an appropriate interval between neoadjuvant cycles and surgery
• Multidisciplinary follow-up: Close coordination among thoracic surgery, oncology, respiratory medicine, and anesthesia

🚀 Place in Clinical Practice

• Neoadjuvant nivolumab + chemotherapy followed by adjuvant nivolumabhas gained support for resectable (EGFR/ALK-negative) NSCLC as a reasonable perioperative standard option.
• Alongside EFS and pCR gains, preserved HRQOL improves patient adherence.
• Patient selection: Patients eligible for surgery, without contraindications to immunotherapy, and with manageable comorbidities.

Note: These data support the FDA approval text; real-world data and maturation of long-term OS should be followed.

🚧 Limitations and Open Questions

• Long-term OS: Longer follow-up may be needed to fully translate the EFS advantage into OS.
• Subgroup details: Analyses by histology, PD-L1 level, and association with minimal residual disease (ctDNA) are important.
• Real-world applicability: Surgical delays, preoperative assessments, and logistical factors vary between centers.

Study 4 — Taletrectinib (Ibtrozi): TRUST-I & TRUST-II

Why does it matter? In ROS1-positive NSCLC,TKIs are highly effective, but resistance and CNS spread remain important problems. Taletrectinibis a ROS1-selective TKI with the potential to penetrate the brain, showing signals of durable responses and satisfactory CNS control in both treatment-naïve and TKI-pretreated populations.

📊 Quick Summary (Key Numbers)

• cORR (TKI-naïve): %85.2 (n = 54); median 20.5 months of follow-up
• Median PFS / DOR (TKI-naïve): Not reached; longest observed PFS 31.6 months and ongoing
• cORR (TKI-pretreated): %61.7 (n = 47)
• CNS/intracranial response: Response rate in patients with brain metastases %66.7
• Safety: Generally manageable; adverse events mostly transient

Note: Data were compiled from updated interim analyses of two phase 2 studies.

🧱 Study Design and Population

• Design: Phase 2, single-arm/multicenter (TRUST-I and TRUST-II)
• Population: Advanced/metastatic ROS1-positive NSCLC; TKI-naïve and TKI-pretreated subcohorts
• Previous treatment: Separate analyses—no previous TKI versus ≥1 previous ROS1 TKI
• Endpoints: cORR (primary), DOR, PFS, OS, safety; intracranial efficacy subanalyses

📈 TRUST-I / II in Numbers

🧠 Cerebral (CNS) Activity: Clinical Importance

In ROS1+ NSCLC, brain metastases may be frequent and determine long-term control. Taletrectinib's intracranial response rate of %66.7suggests CNS penetration and a profile consistent with potential whole-body disease control .

🧯 Safety and Tolerability

• The overall profile is favorable and manageable.
• Drug-related AEs are mostly transientand can be controlled with dose modification/interruption.
• In patients with previous TKI exposure, tolerability also remains sustainable.

🚀 Place in Clinical Practice and Patient Selection

• In first-line TKI-naïve ROS1+ patients, a strong candidate with high cORR.
• In TKI-pretreated patients, meaningful activity also supports use as a post-resistance option.
• With CNS risk or involvement, intracranial activity is clinically attractive.
• Direct comparative data against other ROS1 TKIs are needed to evaluate head-to-head comparisons or sequencing strategies .

🚧 Limitations and Open Questions

• The single-arm and phase 2 design limit conclusions about comparative efficacy .
• Follow-up is not yet mature; median PFS/DOR have not been reached.
• More detailed molecular analyses are needed for the resistance mutation spectrum and subsequent treatment options.

Editor's note: Clinical decisions should consider access/reimbursement and patient preferences, along with center experience and molecular tumor board assessment.

Study 5 — Zidesamtinib (NVL-520): ARROS-1

Why does it matter? In ROS1-positive NSCLC,TKI resistance (particularly G2032R) and CNS spread make long-term disease control difficult. Zidesamtinib, a ROS1-selective, TRK-sparing and CNS-penetrant next-generation TKI, has been evaluated in ARROS-1 phase 1/2. Data suggest durable responses and good tolerability despite multiple previous ROS1 TKIs .

📊 Quick Summary (Key Numbers)

• ORR (after 1–4 ROS1 TKIs): %44
• ORR (after only 1 ROS1 TKI; n=55): %51
• DOR maintenance rate (months 6/12/18): up to 93%.
• Median PFS: Approximately ~24 months (≈ 2 years)
• G2032R resistance mutation: durable activity
• CNS activity: In patients with brain metastases, intracranial responses were observed
• Safety: Generally well tolerated; low dose-reduction and discontinuation rates

Note: Interim data from dose/expansion cohorts; direct comparisons between medicines are hypothesis-generating (because of cross-trial differences).

🧱 Study Design and Population

• Design: Phase 1/2 (ARROS-1); dose escalation + expansion cohorts
• Population: Advanced/metastatic ROS1-positive NSCLC, including multiple previous ROS1 TKI lines
• Endpoints: ORR (primary), DOR, PFS, OS, safety; G2032R and CNS subanalyses

📈 ARROS-1 in Numbers

🧠 CNS Activity: Clinical Importance

The finding that zidesamtinib produces intracranial responses suggests it could be an option in patients with brain metastases and ROS1+ NSCLC, serving in treatment sequencing as a bridge or alternative . CNS control may be a determinant of PFS/OS.

🧯 Safety and Management

• Overall profile: Well tolerated; low dose-reduction/treatment-discontinuation rates
• TRK sparing: May contribute to a potential reduction in off-target neurological AEs
• Close monitoring: Headache, dizziness, GI symptoms, and LFT monitoring (according to center protocols)

🚀 Place in Clinical Practice and Strategy

• Progression after 1 TKI makes this a strong candidate; G2032R positive cases provide a rational setting for its use.
• CNS risk/involvement makes it attractive because of intracranial activity.
• Position in treatment sequencing: Before or after repotrectinib/taletrectinib; direct comparative data are awaited.

Editor's note: Claims of numerical superiority should be interpreted cautiously because of cross-trial differences ; head-to-head trials and real-world data will guide practice.

🚧 Limitations and Open Questions

• Early phase / single arm: Limited conclusions about comparative efficacy
• Follow-up: Some endpoints are not yet mature (e.g., median DOR)
• Resistance biology: Mutation patterns after zidesamtinib and the best sequencing strategy

Study 6 — NADIM ADJUVANT: Nivolumab + Chemotherapy (Adjuvant)

Why does it matter? In completely resected (R0) NSCLC, recurrence is one of the biggest problems. Adjuvant nivolumab + platinum-based chemotherapy aims to go beyond appearing "clear" on pathology and reduce the biological risk of recurrence . NADIM ADJUVANT provides strong signals that this strategy significantly improves disease-free survival (DFS) .

📊 Quick Summary (Key Numbers)

• DFS at month 24: %77.7 (nivolumab + chemotherapy) versus %67.9 (chemotherapy)
• DFS at month 36: %73.3 (nivolumab + chemotherapy) versus %59.9 (chemotherapy)
• Cancer-specific DFS (sensitivity analysis): Statistically significant
• Safety: Manageable; with a profile consistent with previous clinical settings

Note: Completely resected stage IB–IIIA NSCLC population.

🧱 Study Design and Intervention

• Phase: Phase 3 (NCT04564157)
• Population: Completely resected stage IB–IIIA NSCLC
• Arms:
  • Experimental: Adjuvant nivolumab + platinum-based chemotherapy
  • Control: Adjuvant chemotherapy alone
• Endpoints: DFS (primary), cancer-specific DFS, OS, safety

📈 NADIM ADJUVANT in Numbers

🧭 What Do These Results Mean?

In completely resected stage IB–IIIA NSCLC, adjuvant nivolumab + chemotherapyshows potential during the first 2–3 years to substantially reduce recurrence . The persistent separationobserved in DFS may be a promising early indicator of long-term OS gains (final OS maturation must be awaited).

🧯 Safety: Practical Tips

• Immune-related AEs: Screening for thyroid dysfunction, hepatitis, and pneumonitis; early symptom-based intervention
• Chemotherapy toxicities: Supportive treatment for neutropenia, anemia, and nausea, together with dose-delay algorithms
• Follow-up: Imaging at 3–6-month intervals; ctDNA -based MRD monitoring, if available, may help detect recurrence early

🚀 Place in Clinical Practice and Patient Selection

• R0 resection completed, ECOG 0–1 and no contraindication to IO: a rational option in these patients.
• High risk of recurrence (stage II–IIIA, nodal involvement, large tumor size) makes it particularly valuable.
• Multidisciplinary decision: Joint planning and follow-up by thoracic surgery, oncology, and radiology.

🚧 Limitations and Open Questions

• OS maturation: The DFS gain requires follow-up to establish its full translation into long-term OS.
• Biomarkers: More data are needed on PD-L1 levels, ctDNA -based MRD, and subgroup benefit.
• Real-world applicability: Tolerability and treatment completion rates in older patients and those with comorbidities may vary between centers.

Study 7 — HARMONi: Ivonescimab (PD-1/VEGF Bispecific) + Carboplatin/Pemetrexed

Why does it matter? Progression after a third-generation EGFR TKI (e.g., osimertinib) remains a key clinical gapin EGFR-mutant NSCLC. Ivonescimabcombines PD-1 blockade with anti-VEGF activity in the same molecule as a bispecific antibody. HARMONi phase 3 data show that adding ivonescimab to chemotherapy provides significant benefit, particularly in PFS and intracranial control.

📊 Quick Summary (Key Numbers)

• PFS (median): 6.8 months (ivonescimab + chemotherapy) versus 4.4 months (placebo + chemotherapy); HR 0.52, p<0.0001
• OS (median): 16.8 months vs 14.0 months; HR 0.79 — positive trend (particularly Western patients, with nominal significance)
• Intracranial PFS: HR 0.34 (brain metastasis subgroup)
• ORR: %45 vs %34
• Safety: Manageable; any-grade TRAEs: %95.0 vs %93.1

Note: All patients had progression after a 3rd-generation TKI; the platinum/pemetrexed arms were compared.

🧱 Study Design and Population

• Phase: Phase 3 (NCT06396065)
• Population: After a third-generation EGFR TKI, advanced/metastatic EGFRm NSCLC with progression
• Arms:
  • Experimental: Ivonescimab + carboplatin/pemetrexed (induction → pemetrexed ± ivonescimab maintenance)
  • Control: Placebo + carboplatin/pemetrexed (induction → pemetrexed + placebo maintenance)
• Endpoints: PFS (primary), OS, ORR, intracranial PFS, safety

📈 HARMONi in Numbers

🧭 What Do These Results Mean?

As the next step after a TKI, combining chemotherapy with anti-PD-1 + anti-VEGF activity offers advantages in early disease control (PFS) and CNS management . For OS, the positive trend is supported by subanalyses, particularly in Western populations, with nominal significance reached in those analyses; mature OS data should be awaited before a final interpretation.

👥 Patient Selection—When to Use Ivonescimab + Chemotherapy?

• After a 3rd-generation TKI, progression (particularly an early-progression profile)
• Brain metastases present or at high risk (intracranial benefit)
• ECOG 0–1, Hematologic reserve adequate, eligible for chemotherapy
• No contraindication to anti-VEGF (bleeding risk, uncontrolled hypertension, etc.)

🧯 Safety: Practical Management

• Immune-related AEs: dermatitis, thyroiditis, hepatitis, pneumonitis— early screening and algorithm-based management
• Anti-VEGF-related: hypertension, proteinuria, bleeding risk— close monitoring of BP/urinary protein
• Chemotherapy toxicities: neutropenia, anemia, fatigue— G-CSF, dose delays, and supportive treatment

🚧 Limitations and Open Questions

• OS maturation: Longer follow-up is needed for final OS results; subgroup differences should be clarified.
• Biomarkers: The relationship of benefit to PD-L1 level, angiogenic signature, and resistance biology should be investigated.
• Sequencing: Ivonescimab + chemotherapy after a TKI vs has not been directly compared with other IO/anti-VEGF combinations.

Editor's note: These findings provide a framework for considering clinical decisions together with patient preferences, comorbidities, and reimbursement conditions.

Study 8 — ACROSS 2: Aumolertinib + Carboplatin/Pemetrexed (1st Line)

Why does it matter? In EGFR-mutant NSCLC, tumor suppressor gene (TSG) co-mutations (particularly TP53) may be associated with earlier resistance and shorter PFS with TKI monotherapy. ACROSS 2tests whether adding platinum/pemetrexed to aumolertinib improves outcomes in this "high-risk" biology.

📊 Quick Summary (Key Numbers)

• Median PFS: 19.8 months (aumolertinib + chemotherapy) versus 16.5 months (aumolertinib)
• ORR: %70.4 (combination) versus %67.2 (monotherapy)
• Subgroups: TP53 co-mutation and EGFR exon 19 deletion were associated with clear PFS benefit
• Safety: TEAEs were more frequentwith the combination but generally manageable

Note: First-line advanced/metastatic EGFRm NSCLC (1st line); the population with TSG co-mutations is clinically considered high risk .

🧱 Study Design and Intervention

• Phase: Phase 3 (NCT04500717)
• Population: Advanced/metastatic EGFRm NSCLC (including subgroups with identified TSG co-mutations)
• Arms:
  • Combination: Aumolertinib + carboplatin/pemetrexed (induction → aumolertinib ± pemetrexed maintenance)
  • Control: Aumolertinib monotherapy
• Endpoints: PFS (primary), ORR, DOR, OS, safety; TSG co-mutation subanalyses

📈 ACROSS 2 in Numbers

🧭 What Do These Results Mean?

With TSG co-mutations, EGFRm cases tend to progress early on a single TKI. Selecting TPI + chemotherapy from the outset is rational, with the goals of slowing the disease's biological pace and achieving longer PFS . Concurrent chemotherapy may suppress microscopic resistant clones and reduce early escape patterns.

🧯 Safety: Practical Tips

• Hematologic AEs: neutropenia/anemia; dose delay, G-CSF, supportive treatment
• Prerequisites for pemetrexed: folate/B12 and renal function monitoring
• Aumolertinib class effects: rash, diarrhea; early symptom-based intervention

👥 Patient Selection—When to Use a Combination?

• TP53 co-mutation or other TSG alterations (STK11/KEAP1, etc., according to the center's interpretation)
• High tumor burden or risk of early progression anticipated
• ECOG 0–1, with adequate hematologic reserve

Alternative: Monotherapy may be preferred in patients with comorbidities or frailty; PFS should be monitored closely.

🚧 Limitations and Open Questions

• Side-effect burden: Combination toxicity may affect treatment completion rates in real-world practice.
• Sequencing: The best sequence of 2L options after progression (e.g., other TKIs, IO + chemotherapy) is unclear.
• Biomarkers: The magnitude of benefit by TSG subtype (TP53 variant class, etc.) should be described in more detail.

Study 9 — IDeate-Lung01: Ifinatamab Deruxtecan (I-DXd)

Why does it matter? When extensive-stage small cell lung cancer (SCLC) relapses, effective 2nd-line options are limited. I-DXdis a B7-H3-targeted antibody-drug conjugate (ADC) that has attracted attention for its potential to produce rapid responses and a high disease control rate .

📊 Quick Summary (Key Numbers)

• ORR (confirmed): %48.2 (n = 137; 12 mg/kg)
• DCR: %87.6
• TTR (median): 1.4 months — rapid response
• DOR (median): 5.3 months
• PFS (median): 4.9 months
• OS (median): 10.3 months

Note: Clinical benefit was observed regardless of platinum sensitivity and treatment line ; a signal of intracranial activity was reported.

🧱 Study Design and Population

• Phase: Phase 2, single-arm (NCT05280470)
• Population: Previously treated extensive-stage SCLC
• Intervention: I-DXd 12 mg/kg (q3w)
• Endpoints: ORR (primary), DOR, PFS, OS, safety; intracranial subanalyses

📈 I-DXd in Numbers

🧭 What Do These Results Mean?

An ORR of 48% and a rapid response in 1.4 monthsmay provide patients with symptoms/high tumor burden with early clinical relief . PFS of 4.9 months and OS of 10.3 monthsprovide, compared with current 2L options, a competitive profile; the benefit observed irrespective of platinum sensitivity/resistance is particularly noteworthy.

🧯 Safety and Management

• TRAE (any grade): %89.8; Grade ≥3: %36.5 — manageable
• ADC class warnings: Interstitial lung disease/pneumonitis requires early symptom education and a low threshold for evaluation
• Support: For hematologic toxicities, dose delay/reduction, G-CSF; prophylaxis for nausea

🚀 Place in Clinical Practice and Patient Selection

• 2L+ In extensive-stage SCLC, symptom control and rapid responses are needs for which this is a strong option
• CNS involvement makes the reported signal of intracranial activity noteworthy
• High-risk AEs (particularly pneumonitis) require close monitoring and patient education

🚧 Limitations and Open Questions

• Single arm / early phase: Randomized data are required to establish comparative superiority
• OS maturation: More detailed analyses by subgroup (platinum-sensitive/resistant, CNS involvement) are needed
• Sequencing: The best options after an ADC (topo1-ADC → chemotherapy/IO combinations, etc.) should be clarified

Study 10 — ALCHEMIST: Adjuvant Crizotinib (ALK+; Resected NSCLC)

Why does it matter? In early-stage, completely resected ALK-positive NSCLC,whether adjuvant targeted therapy can reduce recurrence risk has long been an important question. ALCHEMIST phase 3 showed that crizotinibcompared with observation did not provide DFS or OS gains, offering a substantial contribution to the evidence concerning adjuvant treatment with this agent: negative evidence .

📊 Quick Summary (Key Numbers)

• Follow-up (median): 58.3 months
• DFS: no benefit — HR 1.06, P=0.86
• OS: not statistically significant — HR 0.49, P=0.26
• Subgroups: By sex, stage, and postoperative RT, no significant benefit
• Toxicity: Similar to the profile in advanced disease; >25% of cases involved treatment interruption

🧱 Study Design and Population

• Phase: Phase 3 (NCT02194738)
• Population: Resected ALK-positive NSCLC (early/intermediate stage; adjuvant setting)
• Arms: Adjuvant crizotinib vs observation
• Endpoints: Time until disease (DFS), OS, safety

📈 ALCHEMIST in Numbers

🧭 What Do These Results Mean?

In early-stage ALK+ NSCLC, adjuvant treatment with crizotinib does not reduce recurrence or prolong survival. In addition, the substantial discontinuation rate raises tolerability concerns in the adjuvant setting. Therefore, crizotinib is not an adjuvant standard treatment option. For adjuvant targeted strategies, randomized data on other agents and long-term results should be followed closely.

🧯 Safety: Practical Notes

• Class effects: GI symptoms, raised liver enzymes, visual disturbances, QT prolongation—symptom tolerance is lower in the adjuvant setting.
• Monitoring: LFTs, ECG (QTc), and close symptom-based follow-up; early dose-modification decisions

🚧 Limitations and Open Questions

• Agent-specific result: Generalizing the negative finding to the entire ALK TKI class may be inappropriate; the agents differ pharmacologically.
• Subgroup nuances: Detailed analyses of stage, nodal status, and interactions with adjuvant chemotherapy/RT are important.
• Future direction: In the adjuvant setting, randomized data are awaited on more potent/modern ALK TKIsand MRD/ctDNA -guided approaches.

Implications for Clinical Practice—Quick Decision Box

Conclusion: In 2025, lung cancer management is being shaped by combinations, CNS control and dynamic biomarkers . Together with center experience, patient preferences, and reimbursement conditions, these findings can be integrated into current standards to maximize patient benefit.

📚 Scientific References

1. Adjuvant Crizotinib Did Not Provide Benefit in ALK+ NSCLC
   Gerber DE, Wang Y, Lange CJ, et al. Phase 3 trial of crizotinib vs observation... IASLC WCLC 2025; Abstract 2559.
   NCT02194738
2. Adjuvant Nivolumab + Chemotherapy (NADIM ADJUVANT)
   Provencio M, Bernabé R, Nadal E, et al. Phase III... IASLC WCLC 2025; Abstract PL03.07.
3. Perioperative Nivolumab (CheckMate 77T)
   Spicer JD, Pulla MP, Cascone T, et al. PROs with perioperative nivolumab... IASLC WCLC 2025; Abstract 3005.
   Cascone T, Awad MM, Spicer JD, et al. N Engl J Med. 2024;390(19):1756-1769. doi:10.1056/NEJM0a2311926.
   FDA Approval
4. Aumolertinib + Chemotherapy (ACROSS 2)
   Wang J. ACROSS 2 phase III... IASLC WCLC 2025; Abstract 2205.
   NCT04500717
5. Ivonescimab + Chemotherapy (HARMONi)
   Goldman JW, Passaro A, Laskin J, et al. Phase 3 HARMONi... IASLC WCLC 2025; Abstract 4808.
   NCT06396065
6. Ifinatamab Deruxtecan (I-DXd; IDeate-Lung01)
   Ahn M-J, Johnson ML, Paz-Ares L, et al. Phase 2 IDeate-Lung01... IASLC WCLC 2025; Abstract OA06.03.
   NCT06203210
7. Taletrectinib (TRUST-I/II)
   NCT04919811, NCT04395677.
8. Iza-bren + Osimertinib (Phase 2)
   Zhou F, Wang Q, Wang H, et al. Phase II study... IASLC WCLC 2025; Abstract 2114.
9. Osimertinib + Chemotherapy (FLAURA2)
   Planchard D, Jänne PA, Kobayashi K, et al. Final OS... IASLC WCLC 2025; Abstract 1956.
   N Engl J Med. 2023;389(21):1935-1948. doi:10.1056/NEJMoa2306434.
   FDA Approval
10. Zidesamtinib (ARROS-1)
    Drilon AE, Cho BC, Lin JJ, et al. ARROS-1 pivotal data... IASLC WCLC 2025; Abstract 4540.
    NCT05118789