Stage IV NSCLC: Biomarker-Directed TherapyKnow the Driver Before Starting Treatment
Before you choose a first-line regimen, you need molecular testing results. Do you have all of them?
Non-negotiable molecular tests before ANY systemic therapy
- 1EGFR mutations — exons 18–21, incl. exon 20 ins — ~50% Asian, ~15% Western adenocarcinoma
- 2ALK rearrangement — IHC D5F3 + FISH or NGS — ~5%
- 3ROS1 fusion — ~2%
- 4RET fusion — ~2%
- 5MET exon 14 skipping mutation — ~3–4%
- 6BRAF V600E — ~2–3%
- 7KRAS G12C — ~13% (mostly Western, squamous rare)
- 8HER2 mutation/amplification — ~3%
- 9NTRK fusion — <1%
- 10PD-L1 TPS — mandatory for all no-driver patients; 22C3 clone for pembrolizumab decisions
Preferred testing: Comprehensive NGS (tissue first; ctDNA if tissue insufficient). PD-L1 IHC (22C3 clone for pembrolizumab; SP263 interchangeable; SP142 is the outlier — underestimates TC staining).
All non-squamous adenocarcinoma MUST have full molecular workup.
Quick Navigation
No actionable driver found — PD-L1 result determines your entire 1L strategy.
- Pembrolizumab monotherapy (KEYNOTE-024: PFS 10.3 vs 6.0 mo; OS 26.3 vs 13.4 mo) — preferred across squamous and non-squamous
- Cemiplimab monotherapy (EMPOWER-Lung1: PFS 8.2 vs 5.7 mo) — alternative to pembrolizumab
- Chemo + IO combination is acceptable but IO monotherapy preferred at ≥50%
- Non-squamous: Pembrolizumab + carboplatin + pemetrexed (KEYNOTE-189: PFS 9.0 vs 4.9 mo; OS 22 vs 10.7 mo)
- Squamous: Pembrolizumab + carboplatin + paclitaxel/nab-paclitaxel (KEYNOTE-407: PFS 6.4 vs 4.8 mo; OS 17.1 vs 11.6 mo)
- Atezolizumab-based combinations: acceptable alternatives
- Non-squamous:Chemo + IO (KEYNOTE-189 showed benefit even in PD-L1 <1% subgroup)
- Squamous: KEYNOTE-407 showed benefit across all PD-L1 subgroups
- IO monotherapy NOT recommendedfor PD-L1 <1%
Chemo Foundation — Platinum Doublet Principles
- Cisplatin vs carboplatin: Cisplatin superior ORR but greater nephrotoxicity, ototoxicity, emesis — carboplatin preferred for elderly, renal impairment, or hearing concerns. Carboplatin AUC 5–6 is standard backbone with pemetrexed or paclitaxel.
- Pemetrexed for non-squamous: Preferred partner (JMDB: pemetrexed + cisplatin vs gemcitabine + cisplatin — superior OS in non-squamous 12.6 vs 10.9m). Premedication: folic acid 400–1000 µg daily, vitamin B12 1000 µg IM q9 weeks, dexamethasone.
- Squamous histology: Gemcitabine or paclitaxel/nab-paclitaxel backbone — pemetrexed is NOT effective in squamous NSCLC.
- Bevacizumab addition (non-squamous): ECOG 4599 — carbo + paclitaxel + bevacizumab: OS 12.3 vs 10.3m (HR 0.79). Add when non-squamous, no haemoptysis, no anticoagulation, no recent haemorrhage.
- Number of cycles: 4–6 cycles induction for non-IO patients. For IO combinations: 4 cycles platinum then maintenance IO ± pemetrexed (non-squamous).
- Elderly / PS2: Carboplatin + weekly paclitaxel or single-agent vinorelbine/gemcitabine. Doublet in PS2 disease-related: reassess after 2 cycles.
Additional Options & Special Populations
- Atezolizumab + bev + carbo + paclitaxel (IMpower150): ORR 64%, PFS 8.3 vs 6.8 mo — particularly useful in EGFR/ALK+ who have progressed on targeted therapy (unique population approval)
- Nivolumab + ipilimumab ± 2 cycles chemo (CheckMate 9LA/227): OS benefit; durable responses especially in high-TMB patients
- STK11/KEAP1 mutations: Associated with IO resistance — consider chemo + IO combination rather than IO monotherapy; clinical trial preferred where available
Maintenance (non-squamous):
Pemetrexed + pembrolizumab continuation after 4 cycles induction
Squamous:
No maintenance benefit with pemetrexed; IO continuation only
Second-Line Options (No Driver, Post-IO Era)
- Post-chemo-IO progression: Docetaxel ± ramucirumab (REVEL: OS 10.5 vs 9.1m, HR 0.86) or docetaxel ± nintedanib (LUME-Lung1: OS 12.6 vs 10.3m non-squamous)
- IO-naïve 2L: Pembrolizumab (PD-L1 ≥1%, KEYNOTE-010: OS 10.4m); nivolumab (CheckMate 017/057: all-comers, OS HR ~0.70); atezolizumab (OAK: OS 13.8 vs 9.6m, HR 0.73)
- KRAS G12C (2L): Adagrasib (KRYSTAL-1: ORR 43%, PFS 6.5m) or sotorasib (CodeBreak 200: ORR 28%, PFS 5.6m)
- ADC 2L: Dato-DXd vs docetaxel (TROPION-Lung01: PFS 4.4 vs 3.4m HR 0.75; ORR 26% vs 13%) — emerging option especially non-squamous
Key Trial Data
KEYNOTE-024 — Pembrolizumab vs Chemo (PD-L1 ≥50%)
Design: Phase III, 305 pts, PD-L1 TPS ≥50%, no EGFR/ALK, Stage IIIB/IV NSCLC
Pembrolizumab 200 mg Q3W vs platinum-based chemotherapy
PFS: 10.3 vs 6.0 mo (HR 0.50, p<0.001)
OS: 26.3 vs 13.4 mo (HR 0.62; 5-year OS 31.9% vs 16.3%)
ORR: 45.5% vs 27.7%
Toxicity: Grade 3–5 TRAEs 26.6% vs 53.3%
Ref: Reck M et al. NEJM 2016; updated OS NEJM 2019.
KEYNOTE-189 — Pembro + Chemo vs Chemo (Non-squamous)
Design: Phase III, 616 pts, non-squamous Stage IV NSCLC, any PD-L1
Pembrolizumab + carboplatin + pemetrexed vs placebo + carboplatin + pemetrexed
PFS: 9.0 vs 4.9 mo (HR 0.48, p<0.001)
OS: 22.0 vs 10.7 mo (HR 0.56, p<0.001)
ORR: 48.3% vs 19.9%
Benefit across all PD-L1 subgroups, including <1% (OS HR 0.59)
Ref: Gandhi L et al. NEJM 2018; updated Garassino M et al. Lancet Oncol 2020.
KEYNOTE-407 — Pembro + Chemo vs Chemo (Squamous)
Design: Phase III, 559 pts, squamous Stage IV NSCLC, any PD-L1
Pembrolizumab + carboplatin + paclitaxel/nab-paclitaxel vs placebo + chemo
PFS: 6.4 vs 4.8 mo (HR 0.56, p<0.001)
OS: 17.1 vs 11.6 mo (HR 0.71, p=0.0008)
ORR: 58.4% vs 35.6%
Benefit across all PD-L1 subgroups
Ref: Paz-Ares L et al. NEJM 2018; updated OS NEJM 2020.
EMPOWER-Lung1 — Cemiplimab vs Chemo (PD-L1 ≥50%)
Design: Phase III, 710 pts, PD-L1 TPS ≥50%, Stage IIIB/IV NSCLC
Cemiplimab 350 mg Q3W vs investigator-choice platinum-based chemo
PFS: 8.2 vs 5.7 mo (HR 0.54, p<0.0001)
OS: 22.1 vs 14.3 mo (HR 0.68, p=0.0022)
ORR: 39.2% vs 20.4%
Ref: Sezer A et al. Lancet 2021.
EGFR-mutated — Ex19del or L858R? That distinction shapes 1L intensity.
1L Options — Full Trial Comparison (FLAURA / FLAURA2 / MARIPOSA)
| Factor | FLAURA | FLAURA2 | MARIPOSA |
|---|---|---|---|
| Publication | NEJM 2018 / 2020 | NEJM 2023 / WCLC 2025 (Final OS) | NEJM 2024 / WCLC 2025 (Updates) |
| Phase | III | III | III |
| Region | Global | Global | Global |
| Population | EGFRm Ex19del / L858R | EGFRm Ex19del / L858R | EGFRm Ex19del / L858R |
| Intervention | Osimertinib 80mg OD | Osimertinib + Carbo/Cis + Pem | Amivantamab + Lazertinib |
| Control | Gefitinib / Erlotinib | Osimertinib monotherapy | Osimertinib monotherapy |
| Primary Endpoint | PFS | PFS | PFS |
| PFS (HR) | 18.9 vs 10.2m (HR 0.46) | 25.5 vs 16.7m (HR 0.62) | 23.7 vs 16.6m (HR 0.70) |
| OS (HR) | 38.6 vs 31.8m (HR 0.80) | 47.5 vs 37.6m (HR 0.77) ★ | Interim: HR 0.80 (NR) |
| ORR | 80% | 83% | 80% |
| Asian Benefit | Significant | Significant (Consistent HR) | Significant (Consistent HR) |
| Key Subgroup | Benefit both Ex19/L858R | Greatest benefit: L858R + CNS | Benefit both; MET-driven? |
| Toxicity | Rash, diarrhea (well-tolerated) | Anemia, neutropenia, fatigue | IRR, rash, paronychia, VTE (40%) |
| Discontinuation | 13% | 11% (Osi), 48% (chemo) | 10% (Laz), 10% (Ami) |
| Route | 100% oral | Oral + IV (q3w) | Oral + SC (monthly)* |
| FDA Approval | 2018 | Feb 2024 | Aug 2024 |
| HK HA Status | Samaritan Fund (SF) | SF (Osi) + Standard (Chemo) | Self-Financed (Expected SF 2026) |
★ Longest median OS reported in 1L EGFRm NSCLC to date. *SC formulation of amivantamab reduces infusion reactions vs IV.
Clinical Decision Framework — Which 1L Option?
| Factor | Osimertinib Monotherapy | Osi + Chemo (FLAURA2) | Ami + Laz (MARIPOSA) |
|---|---|---|---|
| Best For | Low tumor burden, Ex19del, Elderly/frail, Toxicity-averse | L858R, CNS disease, High tumor burden, Fit for chemo | L858R, Fit, IV/SC acceptable, VTE manageable |
| Primary Advantage | Quality of life, 100% oral, Low toxicity, Well-established | Longest median OS (47.5m), proven CNS control | Widening survival curve, potential delay of resistance |
| Main Drawback | Early resistance in high-risk molecular subgroups | Myelosuppression (anemia, neutropenia), IV chemo | VTE risk (40%), Skin/nail toxicity, Infusion reactions |
| Oral vs IV | 100% oral | Oral + IV q3w | Oral + SC monthly |
| HK Funding | SF (Samaritan Fund) | SF (Osi) + Standard (Chemo) | Self-Financed |
Clinical Decision Rules
- Ex19del, low burden, elderly/frail, oral preference: → Osimertinib monotherapy
- L858R, CNS disease, high tumour burden, fit for chemo: → Osimertinib + chemo (FLAURA2) — longest median OS 47.5 months
- L858R, fit, tolerates IV/SC, VTE-acceptable: → Amivantamab + lazertinib (MARIPOSA)
- IO is contraindicated as 1L in EGFRm: Targeted therapy takes priority regardless of PD-L1 expression (even TPS 100%).
Post-Osimertinib Resistance — Re-biopsy Mandatory (Tissue + ctDNA complementary)
| Resistance Mechanism | Frequency | Detection | Treatment Strategy | Key Data |
|---|---|---|---|---|
| MET amplification | ~25% | NGS / FISH | Osimertinib + savolitinib (SACHI) or tepotinib (INSIGHT-2) | SACHI: PFS 8.2 vs 4.5m, HR 0.34; ORR 58% |
| C797S mutation | ~10–15% | ctDNA / NGS | Trans-config: 1st-gen TKI + osimertinib; Cis-config: no approved strategy — clinical trial | Limited clinical data; depends on cis/trans with T790M |
| HER2 amplification | ~5–10% | NGS / FISH | T-DXd (DESTINY-Lung02) or osimertinib + tucatinib (ORCHARD) | T-DXd: ORR 49–56%, PFS 9.9m |
| BRAF V600E (acquired) | ~2–3% | NGS | Osimertinib + dabrafenib + trametinib | ESMO 17P: ORR 42.5%, PFS 8.5m HR 0.38 |
| RET fusion (acquired) | ~1–2% | NGS | Osimertinib + selpercatinib | ORR ~50%, DCR 83% |
| SCLC transformation | ~5–10% | Tissue re-biopsy mandatory | Platinum + etoposide; tarlatamab 2L | EP regimen: ORR 40–70%; tarlatamab mOS 14.3m |
| Squamous transformation | ~3% | Tissue re-biopsy | Immunotherapy + chemo per squamous protocol | Limited data; treat as primary squamous |
| Unknown / polyclonal | ~30–40% | — | Amivantamab + chemo (MARIPOSA-2); or ADC (Sac-TMT, HER3-DXd, Dato-DXd) | MARIPOSA-2: PFS 6.3 vs 4.2m, HR 0.48; OptiTROP-04: PFS 8.3m |
Post-Osimertinib ADC / Chemo-Targeted Options
| Trial | Drug/Regimen | Phase | Population | PFS (HR) | ORR | Main Toxicity | FDA Status | HK HA |
|---|---|---|---|---|---|---|---|---|
| MARIPOSA-2 | Amivantamab + Carbo + Pem | III | Post-Osi EGFRm | 6.3 vs 4.2m (HR 0.48) | 64% | Hematologic, Rash, VTE | Approved Oct 2023 | SFI (PAP/Capping) |
| HERTHENA-Lung02 | HER3-DXd (Patritumab-DXd) 5.6mg/kg | III | Post-TKI EGFRm | 6.4 vs 3.7m (HR 0.77) | ~30–40% | Nausea, ILD (5%) | Breakthrough / Priority | SFI (1+ mechanism) |
| TROPION-Lung05 | Dato-DXd (Datopotamab-DXd) 6mg/kg | II (Pivotal) | Pretreated actionable NSCLC | 5.8m (single arm) | 43.6% (EGFR sub) | Stomatitis (60%), Rash | Filed / Fast Track | SFI |
| OptiTROP-Lung03 | Sac-TMT 5mg/kg Q2W | III | EGFRm post-TKI + Chemo | 6.9 vs 2.8m (HR 0.30) | 45% vs 16% | Neutropenia, Stomatitis | NMPA Approved (China) | SFI (1+ mechanism) |
| OptiTROP-Lung04 | Sac-TMT 5mg/kg Q2W | III | EGFRm post-TKI | 8.3 vs 4.3m (HR 0.49) | 60% vs 43% | Neutropenia, Stomatitis | FDA/EMA (Pending/Priority) | SFI (1+ mechanism) |
Sac-TMT = sacituzumab tirumotecan; ILD rate notably low/0% in OptiTROP studies. OS OptiTROP-Lung03: 20.0 vs 11.2m (HR 0.45); OptiTROP-Lung04: NR vs 17.4m (HR 0.60).
MET Amplification as Osimertinib Resistance — Trial Data
| Trial | Phase | Region | Intervention | Control | PFS (HR) | ORR | OS (Months) | Molecular Marker | Approval |
|---|---|---|---|---|---|---|---|---|---|
| SACHI | III | China (Asian focus) | Savolitinib + Osi | Platinum-Pem | 8.2 vs 4.5m (HR 0.34) | 58% vs 34% | 22.9 vs 17.7m | MET Amp (FISH/IHC) | NMPA Approved 2025 |
| SAFFRON | III | Global | Savolitinib + Osi | Platinum-Pem | 9.2 vs 4.8m (HR 0.38) | 61% vs 35% | HR 0.72 (immature) | MET Amp (FISH 10+) | FDA Filed / HK '1+' |
| SAVANNAH | II (Registrational) | Global | Savolitinib + Osi | N/A (single arm) | 7.2m | 49% (High MET) | ~20.0m | IHC 90+ or FISH 10+ | Breakthrough |
| INSIGHT 2 | II | Global | Tepotinib + Osi | N/A (single arm) | 5.4m | 50% (FISH+) | NR | FISH (GCN ≥5) | Phase II Data |
SCLC Transformation After Osimertinib — Treatment Options
| Regimen | Strategy | Trial | ORR | mPFS | mOS | Main Toxicity | FDA Status |
|---|---|---|---|---|---|---|---|
| Platinum + Etoposide (EP) | Current SOC | Extrapolated from 1L SCLC | 40–70% (short-lived) | 4–6m | 9–11m | Myelosuppression, alopecia | Approved |
| Tarlatamab (DLL3-BiTE) | Emerging 2L targeted (DLL3) | DeLLphi-301 (Ph II/III) | 40% (DLL3+) | 4.9m | 14.3m | Cytokine release (CRS) | Approved May 2024 |
| Ifinatamab-DXd (I-DXd) | Emerging B7-H3 ADC | IDYLLIC-01 (Ph II) | 52% | 5.6m | 12.2m | Neutropenia, ILD (low) | Breakthrough |
Tissue re-biopsy is mandatory to diagnose SCLC transformation. Tarlatamab: DLL3 expression prevalent in Asian populations. I-DXd: B7-H3 broadly expressed in SCLC transformation.
EGFR Exon 20 Insertion — Separate Algorithm
Standard 3rd-gen TKIs (osimertinib, gefitinib, erlotinib) largely ineffective against Exon 20 insertions
Biology: exon 20 insertions shift the C-helix inward, creating a compact binding pocket — sterically excludes most TKIs. Represents ~5–10% of all EGFR mutations.
- 1L — Preferred: Amivantamab + platinum + pemetrexed (PAPILLON: PFS 11.4 vs 6.7m, HR 0.40; ORR 73% vs 47%; FDA approved August 2024). Anti-EGFR/MET bispecific antibody uniquely active against exon 20 steric conformation.
- 2L — Post-chemo: Amivantamab monotherapy (ORR 40%, FDA approved 2021 2L); mobocertinib (ORR 28%, PFS 7.3m — FDA withdrew, still used HK/global)
- Emerging: DXd-based regimens (T-DXd exon 20 cohort, HER3-DXd) under investigation in post-amivantamab setting
- Note: Near-loop insertions (before A767) vs far-loop insertions (after A767) may have different sensitivity profiles. Sanger sequencing alone may miss some insertions — use NGS.
Uncommon EGFR Mutations (G719X, L861Q, S768I)
- Afatinib: LUX-Lung 2/3/6 pooled ORR 71.1% — preferred for these uncommon mutations; 2nd-gen broader kinase coverage
- Osimertinib: Limited data; reasonable alternative given improved toxicity profile vs afatinib
- T790M positivity: Uncommon in de novo — but these mutations can co-exist; re-biopsy at progression to identify T790M
Key Trial Data (Expandable)
FLAURA — Osimertinib vs Standard EGFR-TKI (1L)
Design: Phase III, 556 pts, EGFR Ex19del/L858R, Stage IIIB/IV, treatment-naïve
Osimertinib 80mg QD vs erlotinib/gefitinib
PFS: 18.9 vs 10.2 mo (HR 0.46, p<0.001)
OS: 38.6 vs 31.8 mo (HR 0.80, p=0.046)
CNS PFS: NR vs 11.2 mo (HR 0.48)
Intracranial ORR: 91% vs 68%
Ref: Soria JC et al. NEJM 2018; Ramalingam SS et al. NEJM 2020 (OS).
FLAURA2 — Osimertinib + Chemo vs Osimertinib Mono (1L)
Design: Phase III, 557 pts, EGFR Ex19del/L858R, Stage IV (incl. CNS mets)
Osimertinib 80mg + carboplatin/cisplatin + pemetrexed vs osimertinib mono
PFS: 25.5 vs 16.7 mo (HR 0.62, p<0.001)
OS (WCLC 2025 final): 47.5 vs 37.6 mo (HR 0.77, p=0.0044)
L858R subgroup OS: 45.7 vs 32.6 mo (HR 0.74) — greatest benefit
Ex19del subgroup OS: HR 0.80 (less pronounced)
CNS PFS HR: 0.47 — particular benefit with brain metastases
Toxicity: Grade ≥3 AEs 64% vs 27%; discontinuation rate: 11% (Osi) and 48% (chemo component)
Ref: Planchard D et al. NEJM 2023; OS update WCLC 2025.
MARIPOSA — Amivantamab + Lazertinib vs Osimertinib (1L)
Design: Phase III, 1,074 pts, EGFR Ex19del/L858R, treatment-naïve
Amivantamab (IV or SC) + lazertinib 240mg QD vs osimertinib 80mg QD
PFS: 23.7 vs 16.6 mo (HR 0.70, p<0.001)
OS (interim, WCLC 2025): HR 0.80 — not yet mature
ORR: 86% vs 85%
VTE rate: ~37–40% (anticoagulation prophylaxis often used; MARIPOSA VTE sub-study ongoing)
Infusion reactions: ~67% first IV infusion (SC formulation substantially reduces rate)
Ref: Cho BC et al. NEJM 2024; updates WCLC 2025.
MARIPOSA-2 — Amivantamab + Chemo ± Lazertinib vs Chemo (Post-Osi)
Design: Phase III, 657 pts, EGFR+ progressed on osimertinib
Amivantamab + carboplatin + pemetrexed ± lazertinib vs carbo + pem
PFS (amivantamab + chemo arm): 6.3 vs 4.2 mo (HR 0.48, p<0.001)
ORR: 64% vs 36%
OS (interim): 16.0m; HR 0.77 trend
DCR: 86%; DoR: 6.9m
Note: Triple combination (amivantamab + lazertinib + chemo) NOT recommended — excess toxicity without additional PFS benefit
HK HA: SFI with PAP/Capping mechanism
Ref: Passaro A et al. NEJM 2023; Ann Oncol 2024 updates.
OptiTROP-Lung04 — Sac-TMT vs Platinum + Pemetrexed (Post-EGFR-TKI)
Design: Phase III, EGFRm (Ex19/L858R) post-TKI, Sac-TMT 5mg/kg Q2W vs carbo + pem
PFS: 8.3 vs 4.3 mo (HR 0.49, p<0.001)
OS: NR vs 17.4 mo (HR 0.60)
ORR: 60% vs 43%
18-month OS rate: 65%
ILD rate: 0% — notably absent (important safety advantage over T-DXd)
Asian population: High benefit; major study site China/Asia
Approval: FDA/EMA Pending/Priority Review
Ref: Zhou C et al. NEJM/ESMO 2025.
OptiTROP-Lung03 — Sac-TMT vs Docetaxel (Post-TKI + Chemo)
Design: Phase III, EGFRm post-TKI and prior platinum-chemo, Sac-TMT vs docetaxel
PFS: 6.9 vs 2.8 mo (HR 0.30)
OS: 20.0 vs 11.2 mo (HR 0.45)
ORR: 45% vs 16%
18-month OS rate: 68%
ILD rate: 0% — consistent with Lung04
Approval: NMPA Approved (China 2025); HK SFI 1+ mechanism
Ref: BMJ / ELCC 2026.
PAPILLON — Amivantamab + Chemo vs Chemo (EGFR Exon 20 Ins, 1L)
Design: Phase III, 308 pts, EGFR exon 20 insertion, treatment-naïve
Amivantamab + carboplatin + pemetrexed vs carbo + pem
PFS: 11.4 vs 6.7 mo (HR 0.40, p<0.001)
OS: HR 0.67 (interim, not mature)
ORR: 73% vs 47%
FDA approved: August 2024 for EGFR exon 20 insertion, 1L
Ref: Zhou C et al. NEJM 2023.
SACHI — Osimertinib + Savolitinib vs Platinum-Pem (Post-Osi MET amp)
Design: Phase III (China-focused), EGFR+ progressed on osimertinib with MET amplification
Osimertinib 80mg + savolitinib 300–600mg QD vs platinum + pemetrexed
PFS: 8.2 vs 4.5 mo (HR 0.34, p<0.001)
ORR: 58% vs 34%
OS: 22.9 vs 17.7m (trend)
Asian benefit: Highly significant (primary study site)
Approval: NMPA Approved 2025; SAFFRON (global Phase III ongoing)
Ref: Yang JC et al. Lancet 2024.
HERTHENA-Lung02 — HER3-DXd (Patritumab Deruxtecan) vs Platinum-Pem (Post-TKI)
Design: Phase III vs platinum + pemetrexed, post-EGFR TKI (any line)
HER3-DXd 5.6 mg/kg Q3W
PFS: 6.4 vs 3.7 mo (HR 0.77) — significant improvement
ORR: ~30–40% vs 16%
ILD rate: ~26% any grade; ~5% Grade ≥3 — monitoring required; lower rate vs T-DXd 6.4 mg/kg
HK HA: SFI (1+ mechanism)
Ref: Yu HA et al. WCLC 2024 / ELCC 2026.
Viva Cases — EGFR
🎓 Viva Q: A 58-year-old never-smoker with L858R EGFRm NSCLC and 2 brain metastases. PS1. Which 1L regimen and why?
🎓 Viva Q: Patient on osimertinib 1L progresses after 18 months. ctDNA shows MET amplification (GCN 12 by FISH). What next?
🎓 Viva Q: Post-osimertinib progression — no identified resistance mechanism on NGS. Which ADC to choose and why?
🎓 Viva Q: EGFR exon 20 insertion NSCLC — patient asks about 'targeted therapy'. What do you explain?
🎓 Viva Q: When should SCLC transformation be suspected and how do you confirm it?
ALK+ — lorlatinib, alectinib, or brigatinib? The CROWN 5-year data changed the calculus.
| Trial | Drug | PFS | OS | Notes |
|---|---|---|---|---|
| CROWN (5yr) | Lorlatinib | NR (HR 0.19) | NR (HR 0.81) | 60-month PFS rate 60%; best CNS; hyperlipidaemia >90% |
| ALEX (final) | Alectinib | 34.8m (HR 0.43) | 81.1m (HR 0.78) | Longest mature OS data; photosensitivity, bradycardia |
| ALTA-1L | Brigatinib | 24.0m (HR 0.49) | NR (HR 0.81) | Early pulmonary events (days 1–7); start 90mg × 7d then 180mg |
Clinical Decision Rules
- Brain metastases at diagnosis: Lorlatinib preferred (highest CNS activity, CROWN intracranial ORR 82%; intracranial CR rate 71%)
- No brain metastases: Alectinib (excellent efficacy, mature OS data 81.1m in ALEX final, better CNS toxicity profile); lorlatinib also acceptable
- Fit patient wanting maximum PFS: Lorlatinib (HR 0.19, PFS not reached at 5 years)
- Lorlatinib CNS effects: Counsel all patients about cognitive slowing, mood changes (~30%); start statin proactively for hyperlipidaemia (virtually all patients)
Toxicity Profiles
Lorlatinib — Toxicity Profile
- Hyperlipidaemia: ≥90% — statins required in virtually all patients; monitor fasting lipids baseline and q4-8 weeks
- Weight gain: Common, often significant (median +5–7 kg); counsel patients proactively
- CNS effects: Mood changes (depression, anxiety), cognitive slowing, somnolence (~30%); dose-dependent; may require dose reduction or psychiatric support
- Peripheral neuropathy: Sensorimotor; dose reduction often needed if Grade ≥2
- Oedema: Peripheral and facial; manage with diuretics if needed
Alectinib — Toxicity Profile
- LFT elevation: Transaminase rises; monitor monthly × 3 months then periodically; usually asymptomatic
- Bradycardia: Asymptomatic HR slowing; HR monitoring; avoid negative chronotropes if possible
- Myalgia/CPK elevation: Monitor CK; dose reduce if Grade ≥3 symptomatic
- Photosensitivity: Counsel sun protection (SPF 50+, clothing); avoid direct sunlight during treatment
- Constipation, nausea: Common, manageable with dietary measures
Brigatinib — Toxicity Profile
- Early-onset pulmonary events: Days 1–7; 3% Grade ≥3 ILD/pneumonitis — withhold if suspected; avoid in patients with baseline ILD; start dose: 90mg QD × 7d, then 180mg QD
- Hypertension: ~21% Grade ≥3; antihypertensives required; monitor BP regularly
- CPK elevation: Monitor; dose-reduce if symptomatic myopathy
- Visual disturbance: Rarely; ophthalmology referral if persistent
Post-ALK TKI Progression
- Post-alectinib or brigatinib: Lorlatinib (ORR 48% in phase II; broad compound ALK mutation coverage including G1202R); re-biopsy to characterise resistance
- Post-lorlatinib: Very limited options; clinical trial strongly recommended; platinum + pemetrexed backbone is fallback
- Chemotherapy: Platinum + pemetrexed remains backbone for lorlatinib-resistant disease; ORR ~20–30%
CROWN 5-Year Update — Lorlatinib vs Crizotinib (1L ALK+)
Design: Phase III, 296 pts, ALK+ Stage IIIB/IV, treatment-naïve
Lorlatinib 100mg QD vs crizotinib 250mg BID
PFS (5yr): NR vs 9.3 mo (HR 0.19, p<0.001)
5-year PFS rate: 60% vs 8%
OS (5yr): NR vs NR (HR 0.81) — not yet significant
Intracranial ORR (pts with baseline brain mets): 82% vs 23%
Intracranial CR rate: 71% vs 8%
Time to intracranial progression (5yr): NR vs 16.4m (HR 0.07)
Ref: Shaw AT et al. NEJM 2020; Solomon BJ et al. J Clin Oncol 2024 (5yr update).
ALEX Final Analysis — Alectinib vs Crizotinib (1L ALK+)
Design: Phase III, 303 pts, ALK+ Stage IV, treatment-naïve
Alectinib 600mg BID vs crizotinib 250mg BID
PFS: 34.8 vs 10.9 mo (HR 0.43, p<0.001)
OS (final, ~8yr follow-up): 81.1 vs 61.5 mo (HR 0.78, p=0.02) — most mature ALK OS data to date
Intracranial ORR (CNS mets): 81% vs 50%
Ref: Peters S et al. NEJM 2017; Mok T et al. Lancet Oncol 2021; OS update ESMO 2023.
ROS1+ — crizotinib was the original, but entrectinib/repotrectinib are now preferred.
Epidemiology: ~2% NSCLC; shares biological overlap with ALK+ (both bind crizotinib); adenocarcinoma histology; younger never-smokers over-represented; CD74-ROS1 and SLC34A2-ROS1 are common fusion partners
Key Biology: ROS1 fusions constitutively activate downstream proliferative pathways (RAS/MAPK, PI3K/AKT). High baseline ORRs (~70–80%) with TKIs. Primary resistance is less common than EGFR but acquired G2032R solvent-front mutation is the dominant resistance mechanism (~40% of progressions).
| Drug | Trial | ORR | mPFS | CNS Activity | Resistance Notes |
|---|---|---|---|---|---|
| Repotrectinib | TRIDENT-1 | 79% (TKI-naïve), 38% (post-criz) | ~NR (TKI-naïve) | Intracranial ORR 89% | PREFERRED — macrocyclic; active vs G2032R, L2026M, D2033N |
| Entrectinib | STARTRK-2 | 67% | 15.7m | Intracranial ORR 79% | PREFERRED — excellent CNS; FDA/EMA approved; less active vs G2032R |
| Crizotinib | PROFILE 1001 | 72% | 19.3m | Limited CNS penetration | Historical — avoid if CNS disease; G2032R resistance 40% |
| Lorlatinib | Off-label | 35–36% | ~9m (post-criz) | Good CNS penetration | Active in some post-criz resistance; off-label in ROS1 |
Sequencing Strategy
- 1L preferred: Repotrectinib (TRIDENT-1: ORR 79% TKI-naïve, PFS not reached; intracranial ORR 89%) — next-gen macrocyclic TKI; active against dominant G2032R resistance mutation; approved FDA 2023
- 1L alternative: Entrectinib (STARTRK-2: ORR 67%, mPFS 15.7m; intracranial ORR 79%) — preferred if repotrectinib unavailable; excellent CNS coverage
- Post-crizotinib: Entrectinib or repotrectinib — both active in crizotinib-pretreated patients
- Post-entrectinib: Repotrectinib — active against G2032R solvent-front mutation (most common acquired resistance in ROS1); ORR 38% in 1-prior TKI setting
- Lorlatinib: Activity in ROS1+ post-crizotinib (ORR 35–36%) — off-label but a recognised option; shares compound mutations coverage with ALK
- Post-repotrectinib: Very limited options; clinical trial strongly recommended; platinum-based chemotherapy as fallback
TRIDENT-1 — Repotrectinib in ROS1+ NSCLC
Design: Phase I/II, basket trial, ROS1+ NSCLC, TKI-naïve and TKI-pretreated cohorts
TKI-naïve cohort: ORR 79%; mPFS not reached; intracranial ORR 89% (pts with measurable CNS lesions)
1-prior TKI cohort: ORR 38% (post-crizotinib); active against G2032R (ORR ~48% in G2032R+)
2-prior TKI cohort: ORR 28%
Dose: 160mg QD × 14d then 160mg BID (intra-patient dose escalation design)
Toxicity: Dizziness, dysgeusia, paresthesia (class effect); generally well-tolerated
FDA approved: November 2023 (1L and post-prior ROS1 TKI)
Ref: Drilon A et al. NEJM 2024.
STARTRK-2 — Entrectinib in ROS1+ NSCLC
Design: Phase II basket trial, ROS1+ NSCLC; pooled analysis with STARTRK-1/ALKA-372-001
ORR: 67%; mPFS 15.7m; mOS 44.2m
CNS disease: Intracranial ORR 79% (patients with baseline CNS mets); mCNS DoR 12.9m
Dose: 600mg QD
Toxicity: Dizziness, fatigue, constipation, nausea, weight gain
FDA approved: August 2019 (ROS1+ NSCLC, any line)
Ref: Drilon A et al. Lancet Oncol 2020.
RET fusion — selpercatinib is the standard. What does the LIBRETTO-431 data show?
Epidemiology: ~2% NSCLC; adenocarcinoma histology; KIF5B-RET most common fusion partner (~70%); younger patients, never/light smokers over-represented; KIF5B-RET has somewhat lower sensitivity to selpercatinib than CCDC6-RET fusions
Biology: RET kinase constitutive activation drives proliferation via MAPK/STAT3/PI3K pathways. Multikinase inhibitors (vandetanib, cabozantinib) were historical but had poor selectivity and high toxicity. Selective RET inhibitors (selpercatinib, pralsetinib) achieve superior efficacy with a cleaner side-effect profile.
| Drug | Trial | Setting | ORR | mPFS | mOS | CNS Activity | Approval |
|---|---|---|---|---|---|---|---|
| Selpercatinib 160mg BID | LIBRETTO-431 (Ph III, 1L) | 1L vs SOC | 84% vs 65% | 24.8 vs 11.2m (HR 0.46) | Immature | Intracranial ORR 82% | FDA 2024 (1L); 2020 (2L+) |
| Selpercatinib 160mg BID | LIBRETTO-001 (Ph I/II) | 2L+ post-platinum | 64% | 22.0m | 44.3m | CNS ORR 91% | FDA 2020 |
| Pralsetinib 400mg QD | ARROW (Ph I/II) | 2L+ post-platinum | 70% | 13.3m | Maturing | CNS ORR ~79% | FDA 2020 |
Selpercatinib — Key Features
- 1L preferred (LIBRETTO-431): PFS 24.8 vs 11.2m (HR 0.46); ORR 84%. Significant benefit over SOC (pembro ± chemo or chemo alone based on PD-L1). Excellent CNS penetration — intracranial ORR 82%.
- Toxicity: Hypertension (20% Grade ≥3), LFT elevation (monitor LFTs monthly × 3 months), prolonged QTc (baseline ECG mandatory), peripheral oedema, dry mouth. Avoid strong CYP3A4 inhibitors/inducers.
- Drug interactions: Selpercatinib is a CYP3A4 substrate — co-medication review essential. Proton pump inhibitors reduce absorption — separate dosing or switch to H2 blocker.
Pralsetinib — Alternative Option
- ARROW trial: ORR 70% (treatment-naïve), 61% (post-platinum); PFS 13.3m; mOS maturing
- Toxicity difference: More constipation, less hypertension vs selpercatinib; ILD in ~9%
- Fasting requirement: Must be taken on an empty stomach (≥1h before or ≥2h after food)
After Selective RET Inhibitor Progression
- Clinical trial: Strongly preferred — next-gen RET inhibitors (RET G810 solvent-front resistance), bispecific antibodies in development
- Cross-over (selpercatinib → pralsetinib): May have some activity depending on resistance mechanism; limited data
- Chemotherapy: Platinum-based backbone; IO has limited activity in RET-fusion NSCLC (immunosuppressive microenvironment)
- Multikinase inhibitors (vandetanib, cabozantinib): Historical only — significant toxicity, inferior to selective RET inhibitors; use only if selective agents unavailable
🎓 Viva Q: RET-fusion NSCLC, PD-L1 TPS 80%. Patient asks if pembrolizumab monotherapy is appropriate first-line.
MET ex14 skipping — capmatinib or tepotinib 1L. What's the evidence?
Epidemiology: ~3–4% NSCLC; older patients (median age 70–75); sarcomatoid differentiation common (~20%); adenocarcinoma predominant; generally poorer prognosis than EGFR/ALK; often co-occurs with MET amplification (which is a distinct entity)
Biology: MET exon 14 skipping mutations remove the juxtamembrane domain (encoded by exon 14), preventing normal ubiquitin-mediated MET degradation — leading to receptor accumulation and constitutive signalling. Detection: RNA-based NGS is more sensitive (detects splice variants) than DNA-based NGS alone.
| Drug | Trial | Setting | ORR | mPFS | CNS Activity | Toxicity | Approval |
|---|---|---|---|---|---|---|---|
| Capmatinib 400mg BID | GEOMETRY mono-1 | 1L (TKI-naïve) | 68% | 12.4m | Intracranial ORR 54% | Peripheral edema, nausea, LFT | FDA 2020; 1L |
| Tepotinib 500mg QD | VISION | 1L (TKI-naïve) | 44–46% | 11.0m | Intracranial ORR 55% | Peripheral edema, nausea | FDA 2021; 1L |
| Savolitinib 600mg QD | SAVANNAH subset; Asia | 1L (Asia) | ~50–60% | ~9m | Moderate | Edema, LFT | NMPA approved; HK available |
Treatment Decision Points
- Capmatinib (GEOMETRY mono-1): ORR 68% treatment-naïve; PFS 12.4m; intracranial ORR 54% — preferred for CNS disease due to CNS penetration data. Available globally.
- Tepotinib (VISION): ORR 44–46% (tissue + ctDNA cohort); PFS 11.0m; once-daily dosing may improve compliance in elderly patients.
- Edema management: Both agents cause peripheral edema (20–30% Grade ≥2); prophylactic compression stockings; low-dose diuretics; dose reduce if Grade ≥3
MET amplification ≠ MET exon 14 skipping mutation
MET amplification (high polysomy or gene amplification by FISH) without exon 14 skipping is a distinct biology. Capmatinib/tepotinib have NO approved indication for MET amplification without exon 14 skip. High-level MET amplification (FISH GCN ≥10 or ratio ≥5) may respond but evidence is limited — clinical trial preferred. MET amplification as an EGFR-TKI resistance mechanism (→ SACHI/INSIGHT-2) is a separate scenario covered in the EGFR section.
Post-MET TKI Progression
- Platinum-based chemotherapy backbone; clinical trial strongly recommended
- No approved salvage targeted therapy for post-MET TKI progression
- MET resistance mutations (D1228N, Y1230C/H/S) identified in ~25% progressions — next-gen bivalent MET inhibitors (BMS-1166, elzovantinib) in early clinical trials
- Teliso-V (Telisotuzumab vedotin, anti-MET ADC): emerging option — METHigh overexpression cohort in METex14 patients (see ADC section)
BRAF V600E in NSCLC — dabrafenib + trametinib is standard. New data from 2025–26?
Epidemiology: ~2–3% NSCLC; associated with tobacco smoking (unlike melanoma); adenocarcinoma predominant; median age ~65; V600E accounts for ~50% of BRAF mutations in NSCLC (Class I — constitutively active monomer)
Key distinction: BRAF V600E (Class I) → responds to RAF inhibitor + MEK inhibitor combination. Class II (K601E, L597Q) and Class III (G466V, D594N) → do NOT respond to V600E-targeted therapy; treat per no-driver pathway or enrol in clinical trial.
| Drug/Regimen | Trial | Setting | ORR | mPFS | mOS | Key Notes |
|---|---|---|---|---|---|---|
| Dabrafenib 150mg BID + Trametinib 2mg QD | BRF113928 (Ph II) | 1L and 2L | 64% (1L), 63% (2L) | 10.9m (1L), 10.2m (2L) | 24.6m (1L) | FDA approved NSCLC-specific + tumour-agnostic (V600E) |
| Dabrafenib + Trametinib | ESMO 17P / Real-World (2025–26) | Post-Osi EGFRm with BRAF V600E acquired resistance | 42.5% vs chemo | 8.5 vs 4.8m (HR 0.38) | 21.2m | Triple: Osi + Dab + Tram for acquired resistance |
| Encorafenib 450mg QD + Binimetinib 45mg BID | GEOMETRY BRAF cohort (investigational) | 1L (emerging alternative) | ~60% | ~11m | Maturing | Next-gen RAF + MEK; may have lower pyrexia rate |
Treatment Sequencing
- 1L standard: Dabrafenib + trametinib — ORR 64%, PFS 10.9m, OS 24.6m. FDA approved both NSCLC-specific and tissue-agnostic (BRAF V600E)
- If BRAF targeted therapy not used 1L: Chemo + IO (per PD-L1 TPS) as 1L, then dabrafenib + trametinib in 2L — remains active in pretreated patients (ORR 63% 2L in BRF113928)
- Acquired BRAF V600E in EGFRm post-osimertinib: Triple therapy — osimertinib + dabrafenib + trametinib (ESMO 17P: ORR 42.5%, PFS 8.5m HR 0.38 vs chemo). This is an emerging resistance approach, not yet standard everywhere.
- Post-BRAF-targeted progression: Clinical trial strongly recommended. Possible strategies: PI3K/AKT pathway inhibitors, encorafenib ± MEK inhibitor — all largely investigational
Dabrafenib + Trametinib — Toxicity Management
- Pyrexia: Most common (~50%); typically low-grade fevers; interrupt if Grade ≥2 fever; restart at reduced dose after defervescence
- Rash / palmar-plantar erythrodysaesthesia: Grade 1–2 common; topical emollients; dose reduce if Grade ≥3
- Diarrhea, nausea: Manageable; loperamide for diarrhea
- Uveitis: Rare but important — ophthalmology referral if visual symptoms; hold treatment
- Hyperglycaemia: Monitor blood glucose; diabetic patients need closer monitoring
Note on BRAF non-V600E mutations (Class II & III): Dabrafenib + trametinib is NOT effective for Class II (K601E, L597Q) or Class III (G466V, D594N) BRAF mutations. These have distinct signalling mechanisms (RAS-independent dimer or kinase-impaired). Treat per no-driver pathway (chemo + IO) or enrol in clinical trial investigating RAF inhibitors effective against non-V600 alterations.
HER2 mutation vs HER2 amplification — different diseases, different treatments.
| Drug | Trial | Setting | ORR | mPFS | mOS | ILD Rate | FDA Status |
|---|---|---|---|---|---|---|---|
| T-DXd 5.4 mg/kg Q3W | DESTINY-Lung02 | 2L+ post-platinum | 49–56% | 9.9m | 19.5m | 5% (G≥3) ★ | FDA Accelerated 2022 |
| T-DXd 6.4 mg/kg Q3W | DESTINY-Lung01 | 2L+ | 55% | 8.2m | 17.8m | 13% (G≥3) | Not preferred — higher ILD |
| Zongertinib (Hernexeos) | BEAMION LUNG-1 (Ph Ib) | 2L+ HER2 exon 20 | ~71% | ~12m | Maturing | Low | Breakthrough/Priority |
| Trastuzumab emtansine (T-DM1) | Off-label | 2L+ | ~20–30% | ~4–5m | ~10m | Low | Not approved for NSCLC |
★ Use T-DXd 5.4 mg/kg (not 6.4 mg/kg) — superior safety profile with preserved efficacy (DESTINY-Lung02 primary analysis).
ILD monitoring mandatory: Baseline CT chest before starting T-DXd; repeat CT every 6 weeks × 6 months. Hold immediately for any suspected ILD. See FAQ for Grade-based management.
| Drug | Trial | Population | ORR | mPFS | mOS | Notes |
|---|---|---|---|---|---|---|
| T-DXd 6.4 mg/kg | DESTINY-Lung01 Cohort 1 | HER2 overexp/amp (not mutation) | 26.5% | 5.4m | 12.1m | Weaker evidence vs HER2-mutation cohort |
| Osi + Tucatinib | ORCHARD (HER2 module) | EGFRm + HER2 amp post-Osi | ~20–30% | ~5.5m | 13.8m | For EGFR+HER2 acquired resistance |
HER2 amplification without HER2 mutation is a distinct biology — lower ORR and shorter PFS. Predictive value of IHC 2+ vs 3+ is still being refined for NSCLC.
Emerging HER2-Targeted Agents in NSCLC
- Zongertinib (Hernexeos): Selective HER2 TKI (irreversible kinase inhibitor); BEAMION LUNG-1: ORR ~71% in HER2 exon 20 insertion; Breakthrough Designation; potentially more convenient than ADC
- Sevabertinib: Also selective HER2 TKI targeting exon 20 insertion; early data promising; head-to-head vs zongertinib design under consideration
- 1L role: No HER2-targeted agent approved 1L yet for NSCLC — standard 1L is chemo ± IO; HER2-targeted therapy introduced at progression
KRAS G12C — adagrasib or sotorasib? And should anti-EGFR be added?
Epidemiology: ~13% overall NSCLC (mostly Western populations); adenocarcinoma; strongly associated with tobacco smoking; squamous very rare (<3%); highest frequency in Caucasian populations; ~25% in all KRAS mutations in NSCLC
Biology: KRAS G12C — cysteine-12 substitution creates an allosteric pocket (P2) accessible only in the GDP-bound (inactive) state. Sotorasib and adagrasib covalently bind this pocket, locking KRAS in inactive GDP-bound form. EGFR re-activation is a major bypass mechanism — rationale for adding anti-EGFR agents.
No approved G12C inhibitor in 1L (as of Apr 2026)
Standard 1L treatment = chemo + IO per PD-L1 TPS — identical to no-driver pathway. First-line trials ongoing: KRYSTAL-7 (adagrasib + pembrolizumab vs pembrolizumab in PD-L1 ≥50%), CodeBreak 200 1L arm.
| Drug | Trial | ORR | mPFS (vs docetaxel) | mOS | Approval | Notes |
|---|---|---|---|---|---|---|
| Adagrasib 600mg BID | KRYSTAL-1 (Ph I/II) | 43% | 6.5m (vs 4.3m, HR 0.66) | 12.6m | FDA 2022 — 2L+ | CNS active (intracranial ORR 42%) |
| Sotorasib 960mg QD | CodeBreak 200 (Ph III) | 28% | 5.6m (HR 0.66 vs docetaxel) | 10.6m | FDA 2021 — 2L+ | Direct head-to-head vs docetaxel |
| Adagrasib + cetuximab | KRYSTAL-1 Ph Ib | 46% | 6.9m | Maturing | Not approved — investigational | EGFR bypass blockade rationale |
| Sotorasib + panitumumab | CodeBreak 101 Ph Ib | 30–35% | Maturing | Maturing | Not approved — investigational | Phase III (CAPSTONE) planned |
Adagrasib vs Sotorasib — Key Differences
| Feature | Adagrasib | Sotorasib |
|---|---|---|
| ORR (2L) | 43% | 28% |
| mPFS | 6.5m | 5.6m |
| CNS penetration | Yes — intracranial ORR 42% | Limited CNS data |
| Half-life | ~23h (BID dosing) | ~4–5h (QD dosing) |
| GI toxicity | High (nausea/diarrhea ~75%) | Moderate (~50%) |
| Hepatotoxicity | ~15% Grade ≥3 LFT | ~20% Grade ≥3 LFT |
| CYP interactions | CYP3A4 inhibitor — many interactions | P-gp substrate |
| CNS disease preference | Preferred | Less data |
Co-mutation Impact on Outcomes
- STK11 co-mutation: Markedly worse outcomes on G12C inhibitors AND IO — median PFS ~3–4m; consider earlier clinical trial enrolment
- KEAP1 co-mutation: Also predicts poorer IO and G12C inhibitor response; activates NRF2 antioxidant pathway
- No co-mutations (pure KRAS G12C): Best response rates — prioritise G12C inhibitor after chemo-IO
Emerging — Dual KRAS G12C + SHP2 Inhibition
SHP2 (PTPN11) is a phosphatase upstream of RAS that enables adaptive re-activation of KRAS when G12C inhibitors are used. Adding SHP2 inhibitors (e.g., RMC-4630, JAB-3312) blocks this feedback loop. Early phase I/II data suggest higher ORR with dual inhibition; multiple trials ongoing.
NTRK fusion (<1%) — tissue-agnostic approval. What's the sequencing evidence?
Epidemiology: <1% NSCLC; NTRK1 most common in NSCLC (NTRK2/3 rarer); pan-TRK IHC screening is practical first step — confirm positives by NGS (DNA and/or RNA); adenocarcinoma predominant; younger patients; no strong smoking association
Biology: Neurotrophic receptor tyrosine kinase (NTRK1/2/3) gene fusions → constitutive TRK kinase activation → RAS/MAPK, PI3K/AKT, PLC-γ pathway activation. High ORR with TRK inhibitors — one of the highest biomarker-selected ORRs in oncology. Tissue-agnostic approval reflects remarkably consistent responses regardless of tumour type.
| Drug | Trial | Tumour Types (incl NSCLC) | ORR | mPFS | CNS Activity | Key Resistance | Approval |
|---|---|---|---|---|---|---|---|
| Larotrectinib 100mg BID | NAVIGATE / Phase I/II basket | Pan-tumour (incl NSCLC) | 75% (all tumors); ~100% in NTRK+ NSCLC subset | 28.3m | Intracranial ORR 75% | NTRK G595R/G639C (kinase domain) | FDA 2018 — pan-tumour; NSCLC included |
| Entrectinib 600mg QD | STARTRK-2 / basket | Pan-tumour (incl NSCLC, ROS1, ALK) | 57% (all TRK tumors); 75.8% NSCLC-specific | 11.2m (TRK); 15.7m (NSCLC) | Intracranial ORR 54% | NTRK G595R (same as laro) | FDA 2019 — pan-tumour; NSCLC included |
| Repotrectinib 160mg | TRIDENT-1 (TRK cohort) | Pan-tumour post-TKI | ORR ~58% post-1-prior TKI | Maturing | CNS activity — data emerging | G595R, G667C active (next-gen) | FDA 2023 — 2L+ post-prior TRK TKI |
| Selitrectinib / Cabozantinib | Phase I/II (rescue) | Post-2 TRK TKI | ~20–30% | ~5–6m | Limited | Solvent-front mutations G595R | Not approved; last-resort |
Clinical Pearls
- Larotrectinib preferred if no CNS disease: Historically highest ORR (~75–100% in NTRK+ NSCLC), durable responses (DoR not reached in many series), well-tolerated
- Entrectinib preferred if CNS disease: Demonstrated CNS ORR 54% (better CNS penetration than larotrectinib in some series); also covers ROS1 and ALK fusions — useful if diagnosis uncertain
- Testing strategy: Pan-TRK IHC (clone EPR17341 or A7H6R) as screening — sensitivity ~90%; confirm IHC-positive with RNA-based NGS (detects cryptic fusions DNA-NGS may miss)
- Post-TRK TKI resistance: Repotrectinib covers G595R and G667C kinase domain mutations — preferred next-gen option
- Toxicity: Dizziness, fatigue, nausea, constipation — generally mild; dose reductions rarely needed; both agents have paediatric indications (infantile fibrosarcoma) — reflects TRK biology across age groups
Antibody-drug conjugates — which target, which payload, which patient?
ADC principles: Antibody–drug conjugates combine a targeting antibody with a cytotoxic payload (linker-payload) for selective cancer cell delivery. The bystander effect — payload diffusion to adjacent cells — is particularly relevant for heterogeneous NSCLC tumors. Dual-payload ADCs (emerging) carry two distinct cytotoxic agents.
Key toxicity classes: ILD/pneumonitis (DXd-payload class effect — monitor carefully); stomatitis (most common with Sac-TMT, ~60%); ocular toxicity (some payloads); haematological toxicity.
| ADC | Trial | Setting | ORR | mPFS | mOS | ILD Rate | Key Toxicity |
|---|---|---|---|---|---|---|---|
| Sacituzumab tirumotecan (Sac-TMT) 5mg/kg Q2W | OptiTROP-Lung04 (Ph III) | Post-TKI EGFRm vs carbo+pem | 60% vs 43% | 8.3 vs 4.3m (HR 0.49) | NR vs 17.4m (HR 0.60) | 0% (notable) | Neutropenia, stomatitis |
| Sacituzumab tirumotecan (Sac-TMT) | OptiTROP-Lung03 (Ph III) | Post-TKI+chemo EGFRm vs docetaxel | 45% vs 16% | 6.9 vs 2.8m (HR 0.30) | 20.0 vs 11.2m (HR 0.45) | 0% | Neutropenia, stomatitis |
| Datopotamab deruxtecan (Dato-DXd) 6mg/kg Q3W | TROPION-Lung01 (Ph III) | 2L+ any NSCLC vs docetaxel | 26.4% vs 12.8% | 4.4 vs 3.4m (HR 0.75) | 13.7 vs 11.9m (HR 0.94) | 12% any grade; ~3% G≥3 | Stomatitis (60%), nausea |
| Sacituzumab govitecan (SG) 10mg/kg | Phase II (NSCLC) | 2L+ any NSCLC | ~15–20% | ~4.5m | ~12m | Low | Neutropenia, diarrhea |
Sac-TMT uses a different payload (camptothecin-based CL2A-SN-38 vs DXd in Dato-DXd) — explaining absent ILD signal vs DXd-class agents. TROPION-Lung01 OS benefit marginal; primary PFS endpoint met.
| ADC | Trial | Population | ORR | mPFS | ILD Rate | Status |
|---|---|---|---|---|---|---|
| T-DXd 5.4 mg/kg Q3W | DESTINY-Lung02 | HER2 mutation, 2L+ | 49–56% | 9.9m | 5% G≥3 — PREFERRED DOSE | FDA Accelerated 2022 |
| T-DXd 6.4 mg/kg Q3W | DESTINY-Lung01 | HER2 overexp/amp, 2L+ | 26.5% | 5.4m | 13% G≥3 | Not preferred — higher ILD |
| ADC | Trial | Population | ORR | mPFS | Key Biomarker | Status |
|---|---|---|---|---|---|---|
| Telisotuzumab vedotin (Teliso-V) 1.9mg/kg Q2W | LUMINOSITY (Ph II) | METHigh non-squamous NSCLC, 2L+ | 35–37% | 5.4m | MET IHC H-score ≥225 | Breakthrough; FDA review ongoing |
| Teliso-V + Osimertinib | LUMINOSITY Combo cohort | EGFRm + METHigh post-Osi (acquired MET OE) | ~50% | ~7m | MET OE (IHC) | Phase II data; emerging option |
Teliso-V targets MET overexpression — distinct from MET exon 14 skipping (targeted by capmatinib/tepotinib) or MET amplification (targeted by savolitinib+Osi). Payload = MMAE (tubulin inhibitor); neutropenia and peripheral neuropathy are class effects.
| ADC | Trial | Population | ORR | mPFS | mOS | Status |
|---|---|---|---|---|---|---|
| Ifinatamab deruxtecan (I-DXd/DS-7300) 12mg/kg Q3W | IDYLLIC-01 (Ph II) | SCLC (incl EGFR SCLC transformation), heavily pretreated | 52% | 5.6m | 12.2m | Breakthrough Designation |
I-DXd particularly relevant for SCLC transformation post-EGFR-TKI — SCLC transformation tumors have high B7-H3 expression. See EGFR resistance section.
| ADC | Trial | Population | ORR | mPFS | ILD Rate | Status |
|---|---|---|---|---|---|---|
| Patritumab deruxtecan (HER3-DXd/MK-1022) 5.6mg/kg Q3W | HERTHENA-Lung01 (Ph II) | Post-EGFR-TKI EGFRm | 29.8% | 5.5m | ~12% any grade; 2.6% G≥3 | FDA Breakthrough; Phase III (HERTHENA-Lung02) completed |
| Patritumab deruxtecan 5.6mg/kg | HERTHENA-Lung02 (Ph III) | Post-TKI EGFRm vs carbo+pem | ~30–40% | 6.4 vs 3.7m (HR 0.77) | ~5% G≥3 | Priority Review; SFI HK |
ADC Selection Guide — Post-osimertinib EGFRm Context
| Clinical Scenario | Preferred ADC | Alternative | Avoid | Reason |
|---|---|---|---|---|
| Pre-existing ILD / lung fibrosis | Sac-TMT (0% ILD) | HER3-DXd (2.6% G≥3) | Dato-DXd, T-DXd | DXd payload ILD risk |
| Unknown resistance / polyclonal | Sac-TMT (best PFS data) | HER3-DXd | — | Broad TROP2 expression; no resistance mutation testing needed |
| HER2 mutation | T-DXd 5.4 mg/kg | — | T-DXd 6.4 mg/kg | Lower ILD at 5.4 mg/kg; non-inferior efficacy |
| MET overexpression (METHigh) | Teliso-V + Osi | Teliso-V monotherapy | — | MET OE as resistance mechanism; add Osi for EGFR coverage |
| SCLC transformation | Platinum + etoposide (1L) | Tarlatamab (2L); I-DXd (2L+) | Standard NSCLC regimens | Histological transformation — SCLC biology applies |
| High stomatitis risk / poor oral mucosa | HER3-DXd or T-DXd | — | Sac-TMT, Dato-DXd | Stomatitis >60% with TROP2-targeting TROP2 ADCs |
Brain mets — SRS vs WBRT vs TKI-first? The sequencing question depends on driver status.
Epidemiology: ~20–40% of NSCLC patients develop brain metastases during their disease course; ~10–15% at presentation. Risk higher in adenocarcinoma, EGFR+, ALK+ histologies. Median OS without treatment: 1–3 months (historic); with modern systemic therapy: 10–18 months (driver+), 6–12 months (no driver).
Decision Framework — Initial Management
Driver-positive (EGFR, ALK, ROS1, RET)
- Osimertinib (EGFR): CNS penetration data superior — FLAURA CNS PFS NR vs 11.2m (HR 0.48); intracranial ORR 91% — deferring upfront cranial RT is supported by evidence for asymptomatic brain mets
- Lorlatinib (ALK): CROWN intracranial ORR 82%, intracranial CR rate 71%, time to intracranial progression HR 0.07 — preferred ALK TKI for brain mets
- SRS for 1–3 large/symptomatic lesions alongside TKI; re-assess systemic control before committing to WBRT
- Defer WBRT in driver+ patients: Neurocognitive toxicity outweighs benefit when TKI controls CNS disease; WBRT reserved for leptomeningeal disease or TKI-refractory CNS
No driver / non-targetable driver
- 1–4 lesions, each <3 cm: SRS (RTOG 9508; EORTC 22952) — add WBRT only for salvage or >4 lesions; SRS preserves neurocognition
- 5–10 lesions: SRS increasingly used (Memorial SRS experience); WBRT remains option if SRS technically unfeasible
- >10 lesions or leptomeningeal disease: WBRT or systemic therapy (IO ± chemo); hippocampal-avoidance WBRT + memantine reduces cognitive decline
SRS vs WBRT — Evidence Summary
| Trial | Population | Intervention | Key Finding | Recommendation |
|---|---|---|---|---|
| RTOG 9508 | 1–3 brain mets, any histology | SRS alone vs SRS + WBRT | WBRT improved local control but not OS; QoL worse with WBRT | SRS alone preferred for 1–3 mets |
| EORTC 22952 | 1–3 brain mets post-resection or SRS | Observation vs WBRT | WBRT reduced intracranial failure but did NOT improve OS; neurocognitive toxicity significant | Omit adjuvant WBRT after SRS/surgery |
| NCCTG N107C / CEC.3 | Post-resection 1 met | SRS to cavity vs WBRT | Worse cognitive decline with WBRT (4.5 vs 3.7m to deterioration); OS identical | SRS to resection cavity preferred |
| QUARTZ (UK) | Multiple brain mets, PS variable | WBRT vs optimal supportive care | No OS benefit in poor-PS patients; QoL not improved | WBRT not appropriate for poor-PS non-driver patients |
Radiation Necrosis vs Tumour Recurrence — Differentiation
Clinical challenge: Both appear as enhancing lesions on contrast MRI — clinically indistinguishable in ~20% cases
Radiation necrosis clues: 6–24 months post-SRS; "soap bubble" or stippled enhancement on MRI; high ADC value on diffusion-weighted imaging; low perfusion on DSC-MRI; stable or decreasing over time on clinical observation
Recurrence clues: Any time post-RT; progressive enhancement; high perfusion (rCBV >1.5 on DSC-MRI); spectroscopy: elevated choline/NAA ratio; FET-PET: high uptake ratio
Advanced imaging: MRI perfusion (DSC/DCE) + MRS spectroscopy + FET-PET as a panel — sensitivity/specificity for recurrence ~85% with multimodal approach
Management: Grade 1–2 radiation necrosis: bevacizumab 7.5mg/kg Q3W (± dexamethasone) — resolves in ~60% cases. Grade 3+: surgical resection ± laser interstitial thermal therapy (LITT).
Re-SRS criteria: Confirmed recurrence (not necrosis); lesion <3 cm; ≥3–6 months since prior SRS; cumulative dose constraints met; no evidence of leptomeningeal spread. Each centre uses different dose-volume constraints (V12Gy, Dmax limits).
Progression on Osimertinib with Brain Metastases — Management
- CNS-only progression (extracranial controlled): Continue osimertinib + local CNS treatment (SRS or neurosurgery) — systemic control maintained; re-biopsy not urgently needed
- CNS + systemic progression: Re-biopsy (tissue or ctDNA) to identify resistance mechanism → guide next systemic treatment (see EGFR resistance section)
- Leptomeningeal disease (LMD): High-dose osimertinib 160mg QD (off-label; case series support); intrathecal chemotherapy (methotrexate); WBRT; enrolled clinical trial. Prognosis poor — median OS ~3–6m; careful goals-of-care discussion essential
- Re-SRS for progressive CNS mets on TKI: Can be given for 1–4 new/progressive lesions meeting size/dose criteria. Multiple SRS courses are feasible; cumulative dose-volume constraints must be reviewed with radiation oncology.
🎓 Viva Q: EGFR L858R patient with 3 asymptomatic brain metastases (each 1–1.5 cm). No neurological symptoms. PS1. What is your approach?
🎓 Viva Q: How do you decide between SRS and WBRT for a patient with 5 brain metastases from KRAS G12C NSCLC?
Oligometastatic NSCLC — when and how to use local ablative therapy (LAT)?
Definition of Oligometastatic NSCLC (2026 Consensus)
- Classic oligometastatic (OligoMET): ≤5 metastatic lesions, ≤2–3 organ sites (excluding primary and regional nodes); synchronous (at diagnosis) or metachronous (≥6 months after curative-intent primary treatment)
- Oligoprogressive (OligoPD): ≤3–5 lesions progressing on systemic therapy while majority of disease remains controlled — the "sweet spot" for local therapy while continuing systemic treatment
- Local ablative therapy (LAT) synonyms: SABR (stereotactic ablative radiotherapy), SBRT (stereotactic body RT), local consolidative therapy (LCT), local radical therapy (LRT)
Key Trials in Oligometastatic NSCLC
| Trial | Design | Population | Intervention | Key Outcome | Notes |
|---|---|---|---|---|---|
| SABR-COMET (Phase II) | Randomised | Oligo-mets any histology (1–5 lesions) | SABR (all sites) vs standard care | OS 41 vs 28m (HR 0.57); PFS 12.0 vs 6.0m | Multi-tumour SABR; includes NSCLC (most common histology) |
| NRG-LU002 (Phase II) | Randomised | Stage IV NSCLC 1–4 mets, PS 0–2 | Concurrent LCT (within 30d of systemic) vs sequential LCT (after 3 cycles) | Concurrent LCT: PFS benefit; 1-yr PFS 36% vs 28% | Concurrent > sequential LAT — 'treat early' principle |
| ETOP-CHESS (ETOP 14-18, Phase III) | Randomised | OligoPD on systemic therapy (driver+ or -) | LAT to all PD sites vs systemic switch | Pending (primary endpoint: PFS); interim data suggest LAT arm numerically superior | First Phase III in oligoPD; results awaited 2026 |
| EORTC ICARS (Phase II/III) | Randomised | Oligometastatic NSCLC ≤3 sites | LAT (SABR/surgery) + SOC vs SOC alone | OS benefit in LAT arm (HR 0.65, p=0.04); PFS benefit | Validates LAT benefit in prospective phase II/III — strongest prospective evidence |
| MDACC Phase II (Gomez 2016) | Randomised | Stage IV NSCLC ≤3 mets, response/stable on 1L systemic | Local consolidation + maintenance vs maintenance alone | PFS 11.9 vs 3.9m (HR 0.35); OS 41.2 vs 17.0m (HR 0.40) | Landmark trial — established LCT concept in NSCLC |
| SINDAS (China Phase III) | Randomised | Stage IV NSCLC ≤5 mets, EGFR-mutated | EGFR-TKI + SABR vs EGFR-TKI alone | PFS 20.2 vs 12.5m (HR 0.62); OS 25.5 vs 17.4m (HR 0.68) | Driver-positive oligoMET — LAT + TKI prolongs PFS and OS |
Timing of Local Ablative Therapy — The "Sweet Spot"
Clinical evidence converges on a 3–6 month window after systemic therapy initiation:
- 3–6 months of systemic therapy first: Establish systemic disease control; eliminate occult micro-metastases not visible on baseline imaging; select patients with truly oligometastatic biology (vs those who will develop rapid systemic progression)
- LAT criteria at 3–6 months: ≤5 active lesions (≤3 strongly preferred); all sites technically addressable by SABR/surgery; systemic disease otherwise controlled or responding; PS 0–2
- Concurrent LAT (NRG-LU002 protocol): Delivering LAT within 30 days of starting systemic therapy — showed superior PFS vs sequential (3 cycles then LAT). Practical challenge: requires rapid multidisciplinary planning
- Driver-positive disease (EGFR, ALK): SINDAS shows SABR + TKI superior to TKI alone. For EGFR-mutated oligoMET, combining LAT with osimertinib or alectinib is a valid strategy — multidisciplinary discussion essential
Oligoprogression (OligoPD) on Systemic Therapy
When 1–5 lesions progress on IO, targeted therapy, or chemotherapy while the bulk of disease remains controlled:
- Continue systemic therapy + add LAT to progressing site(s): This avoids premature systemic treatment switch; exploits the concept that oligoPD lesions may represent focally resistant clones while systemic drug still controls the majority
- CNS oligoprogression on TKI: The paradigm case — if 1–3 brain lesions progress on osimertinib while extracranial disease is controlled, SRS to those lesions + continue osimertinib is strongly supported by retrospective series and is standard practice
- Bone oligoprogression: SBRT to 1–3 progressing bone lesions + continue IO/targeted — REMARK trial (bone-targeted SABR) supports this approach
- Systemic PD: If ≥5 sites progress or new distant organ involvement — systemic treatment switch is required, not LAT
Patient Selection for LAT — Practical Checklist
Favourable for LAT:
- ≤5 lesions (≤3 preferred)
- Response/stable on systemic therapy
- ECOG PS 0–1 (PS 2 selectively)
- Metachronous >6 months disease-free interval
- Technically addressable (SABR feasibility confirmed)
Unfavourable for LAT:
- >5 active lesions
- Systemic disease uncontrolled/progressing
- ECOG PS 3–4
- Leptomeningeal disease
- Pleural/pericardial effusion dominant
SABR-COMET Phase II — Multi-tumour SABR vs Standard Care
Design: Phase II randomised, 99 pts, ≤5 metastatic lesions (any histology including NSCLC ~35%), oligometastatic intent, PS 0–1
SABR to all metastatic sites + standard care vs standard care alone
OS: 41.0 vs 28.0 mo (HR 0.57, p=0.09 — hypothesis generating)
PFS: 12.0 vs 6.0 mo (HR 0.47, p=0.001)
5-year OS rate: 42.3% vs 17.7%
Safety: 4 Grade 4–5 events in SABR arm — patient selection and technique quality critical
Ref: Palma DA et al. Lancet 2019; 5-yr update 2020.
SINDAS — EGFR-TKI + SABR vs EGFR-TKI (Oligometastatic EGFR+ NSCLC)
Design: Phase III randomised (China), EGFR-mutated Stage IV NSCLC with ≤5 mets, all sites treated with SABR before TKI
EGFR-TKI + SABR to all sites vs EGFR-TKI alone (historical 1st gen TKIs used)
PFS: 20.2 vs 12.5 mo (HR 0.62, p<0.001)
OS: 25.5 vs 17.4 mo (HR 0.68, p=0.026)
Caveats: 1st-gen TKIs used (pre-osimertinib era); modern repeat with osimertinib needed; applicable principle likely still valid
Ref: Wang XS et al. JAMA Oncol 2022.
🎓 Viva Q: A 52-year-old EGFR wild-type (no driver), PD-L1 60%, with 3 metastatic sites (adrenal, bone, lung) has a complete response in the adrenal and bone after 4 cycles of pembrolizumab + carboplatin + pemetrexed, but the 2cm lung nodule persists. What do you do?
Second-line and beyond: platinum-based salvage, ADCs, and re-challenging IO
At progression: Re-biopsy (tissue or ctDNA) strongly recommended
Both modalities are complementary — ctDNA detects resistance mutations in circulating tumour DNA but misses histological transformation (e.g., SCLC) and focal clonal events. Tissue biopsy of the progressing lesion adds information about histological subtype change, tumour microenvironment, and spatial heterogeneity not captured by liquid biopsy.
2L After Chemo + IO (No Driver)
| Regimen | Trial | PFS | OS | Notes |
|---|---|---|---|---|
| Docetaxel 75mg/m² Q3W | Historical standard | ~3.0m | ~7.0m | ORR 10–15%; backbone for combinations |
| Docetaxel + ramucirumab | REVEL | 4.5 vs 3.0m (HR 0.76) | 10.5 vs 9.1m (HR 0.86) | All histologies; anti-VEGFR2; Grade ≥3 neutropenia 55% |
| Docetaxel + nintedanib | LUME-Lung1 | 3.4 vs 2.7m (HR 0.79) | 12.6 vs 10.3m (HR 0.83, non-sq) | Non-squamous only OS benefit; adenocarcinoma subgroup best |
| Dato-DXd (TROP2 ADC) | TROPION-Lung01 | 4.4 vs 3.4m (HR 0.75) | 13.7 vs 11.9m (HR 0.94) | ORR 26% vs 13%; emerging standard vs docetaxel |
| Sac-TMT (TROP2 ADC) | OptiTROP-Lung01/03 | PFS superior to chemo | Maturing | ORR ~40–54%; strong EGFR+ data in OptiTROP-Lung04 |
| Pembrolizumab (IO-naïve) | KEYNOTE-010 | 3.9 vs 4.0m | 10.4 vs 8.5m (PD-L1 ≥1%) | PD-L1 ≥1%; IO-naïve 2L only; ORR 18% |
| Nivolumab | CheckMate 017/057 | ~2.3–3.5m | OS HR ~0.73 | All-comers; approved regardless of PD-L1 |
| Atezolizumab | OAK | 2.8 vs 4.0m | 13.8 vs 9.6m (HR 0.73) | All-comers; approved 2L+; modest PFS but OS benefit |
2L After IO Progression — Types of Progression Matter
Slow PD on IO (≥6 months response then slow growth):
Clinical evidence supports IO rechallenge in some patients after a washout period. The KEYNOTE-024 retreatment data showed ~29% ORR to pembrolizumab rechallenge in long-term responders who subsequently progressed. This remains experimental — discuss multidisciplinary.
Oligoprogression on IO (1–5 sites while rest controlled):
Continue IO + add LAT/SABR to the progressing lesion(s) — standard approach. Supported by retrospective series and the emerging Phase III ETOP-CHESS trial framework.
Systemic PD on IO (rapid progression, multiple new sites):
Switch systemic therapy — docetaxel ± ramucirumab/nintedanib; ADCs (Dato-DXd, Sac-TMT); or clinical trial. Hyperprogression (~10–15%): identify rapidly; poor PS and high baseline LDH are risk factors. Discontinue IO immediately and switch to salvage chemotherapy.
IO Resistance Mechanisms & Emerging Strategies
| Resistance Category | Mechanism | Emerging Strategy |
|---|---|---|
| Primary IO resistance | Low TMB, immunologically cold tumour, STK11/KEAP1 mutations | IO + anti-angiogenic; IO + ADC combinations; KRAS G12C inhibitors (if G12C+) |
| Acquired IO resistance | Loss of MHC-I antigen presentation, T-cell exhaustion, CAF-mediated immune exclusion | Dual checkpoint blockade (CTLA-4 + PD-1); TIM-3, LAG-3 inhibitors |
| Adaptive resistance (IO) | IFNγ-induced PD-L1 upregulation, regulatory T-cell expansion | Anti-TIGIT (vibostolimab) + IO; bispecific antibodies |
| IO + antiangiogenic (combination) | VEGF suppresses T-cell trafficking; dual blockade may synergise | Atezolizumab + bevacizumab (IMpower150 data); ramucirumab + IO (RELAY data) |
| SCLC transformation | Histological switch in EGFR-mutated NSCLC; NEUROD1/ASCL1 activation | Platinum + etoposide; tarlatamab (DLL3) 2L; IO ± DLL3-targeted |
Next-Generation IO Strategies — Emerging (2026)
- Dual checkpoint blockade (nivolumab + ipilimumab): CheckMate 227 OS benefit (HR 0.79) especially high-TMB (≥10 mut/Mb). CheckMate 9LA: nivo + ipi + 2 cycles chemo vs 4 cycles chemo (OS HR 0.66) — approved 1L all-comers.
- Anti-TIGIT + PD-1 (vibostolimab + pembrolizumab): MK-7684A Phase III; TIGIT expression common in exhausted T cells in NSCLC — potential synergy with PD-1 blockade.
- Anti-LAG-3 (relatlimab + nivolumab): Established in melanoma (RELATIVITY-047); NSCLC trials ongoing. LAG-3 expression enriched in PD-L1-low/negative NSCLC — complementary to PD-1 axis.
- Bispecific antibodies: Ivonescimab (anti-PD-1/VEGF bispecific) — AK112-301 Phase III in China: PFS 11.1 vs 8.3m vs pembrolizumab in PD-L1 ≥1% NSCLC (HR 0.51); HARMONi-2 trial underway globally.
- mRNA cancer vaccines (BNT111, mRNA-4157): Personalised neoantigen vaccines + pembrolizumab — Phase II data in melanoma maturing; NSCLC trials initiated. Not yet practice-changing.
Hyperprogression on IO — Recognition & Management
Hyperprogression (≥2× increase in tumour growth rate; >50% new lesion burden) occurs in ~10–15% initiated on IO checkpoint inhibitors. Associated with: MDM2/MDM4 amplification, EGFR mutations, poor ECOG PS, high baseline LDH. Identify early with 4–6-week imaging if clinically suspected. Discontinue IO; switch to docetaxel ± ramucirumab or ADC.
REVEL — Docetaxel + Ramucirumab vs Docetaxel (2L, All-NSCLC)
Design: Phase III, 1,253 pts, Stage IV NSCLC progressed after platinum-based chemotherapy (any PD-L1, any driver)
Docetaxel 75mg/m² + ramucirumab 10mg/kg Q3W vs docetaxel + placebo
PFS: 4.5 vs 3.0 mo (HR 0.76, p<0.001)
OS: 10.5 vs 9.1 mo (HR 0.86, p=0.023)
ORR: 23% vs 14%
Grade ≥3 neutropenia: 49% vs 40% — G-CSF support recommended
Benefit across all histologies including squamous (OS HR 0.86)
Ref: Garon EB et al. Lancet 2014.
TROPION-Lung01 — Dato-DXd vs Docetaxel (2L+, Non-Squamous)
Design: Phase III, 604 pts, Stage IV non-squamous NSCLC, ≥1 prior platinum-based therapy
Datopotamab deruxtecan (Dato-DXd) 6mg/kg Q3W vs docetaxel 75mg/m² Q3W
PFS: 4.4 vs 3.4 mo (HR 0.75, p=0.004)
OS: 13.7 vs 11.9 mo (HR 0.94 — not statistically significant)
ORR: 26.4% vs 12.8%
EGFR-mutated subgroup (post-TKI): PFS HR 0.87 — less benefit than non-EGFR population
ILD rate: 10.2% any grade (2.9% Grade ≥3) — lower than T-DXd
Oral mucositis: 34% (any grade) — unique Dato-DXd toxicity
Ref: Awad MM et al. NEJM 2024.
CheckMate 9LA — Nivolumab + Ipilimumab + 2 Cycles Chemo vs 4 Cycles Chemo (1L)
Design: Phase III, 719 pts, Stage IV NSCLC (any PD-L1, any histology, no driver), treatment-naïve
Nivo 360mg Q3W + Ipi 1mg/kg Q6W + carbo/plat + paclitaxel/pem × 2 cycles vs 4 cycles chemo
OS: 15.6 vs 12.2 mo (HR 0.84, p=0.038) at 2yr follow-up
3-year OS rate: 27% vs 19%
PFS: 6.7 vs 5.0 mo (HR 0.67)
ORR: 38% vs 25%
Benefit independent of PD-L1 TPS — advantage over IO monotherapy approaches
Ref: Paz-Ares L et al. NEJM 2021; 3-yr update J Clin Oncol 2022.
Clinical FAQs
What is the preferred 1L treatment for EGFR L858R vs Ex19del?
Is lorlatinib always better than alectinib for ALK+ NSCLC?
What comes after osimertinib at progression?
When can IO be used in driver-positive NSCLC?
Does PD-L1 matter in KRAS G12C NSCLC?
How do I manage ILD with T-DXd (trastuzumab deruxtecan)?
Is a KRAS G12C inhibitor approved first-line?
Can IO be combined with targeted therapy in NSCLC?
When is EGFR exon 20 insertion treated differently from classic EGFR mutations?
What is the definition of oligometastatic NSCLC and when should local ablative therapy be given?
When should WBRT be preferred over SRS for brain metastases in NSCLC?
How do sotorasib and adagrasib compare for KRAS G12C NSCLC?
Which ADC is preferred for post-EGFR-TKI NSCLC in 2026?
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Clinical Disclaimer: These guidelines are intended for qualified healthcare professionals. Content reflects NCCN NSCLC 3.2025 and ESMO Living Guideline v1.3 Feb 2026. Treatment decisions must be individualised; consult local formulary, funding pathways, and the full trial data before prescribing. Last reviewed April 2026.