Non-small-cell lung cancer: lines of therapy
21 standard-of-care settings across 4 lines and 13 biomarker subgroups. Rows come from the cancer page's standard of care; the grid places each on its line and subgroup.
| Line | All comers | ALK | BRAF | EGFR | EGFR exon 20 | HER2 | HR-positive | KRAS G12C | MET | NTRK | PD-L1 | RET | ROS1 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Screening, prevention and diagnosis | 2 | · | · | · | · | · | · | · | · | · | · | · | · |
| Early / localised | 1 | · | · | 1 | · | · | · | · | · | · | · | · | · |
| Locally advanced | 1 | · | · | 1 | · | · | · | · | · | · | · | · | · |
| Advanced, first line | 2 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 2 | 1 | 1 |
Screening, prevention and diagnosis
| Subgroup | Setting | Approach | Products and trials | Guideline | Evidence |
|---|---|---|---|---|---|
| All comers | Screening | Annual low-dose CT for high-risk smokers (NLST, NELSON); AI nodule scoring emerging. | NCCN Guidelines: Non-Small Cell Lung Cancer | 40 | |
| All comers | Screening (age 50-80, ≥20 pack-years) | Annual low-dose CT with Lung-RADS reporting; AI nodule scoring emerging; robotic bronchoscopy for peripheral nodule biopsy. | 83 |
Early / localised
| Subgroup | Setting | Approach | Products and trials | Guideline | Evidence |
|---|---|---|---|---|---|
| All comers | Stage I-II resectable | Lobectomy or segmentectomy (small peripheral) with nodal staging; SBRT if inoperable. Stage IB-IIIA: neoadjuvant chemo-IO (CheckMate 816) or perioperative chemo-IO (KEYNOTE-671); adjuvant osimertinib if EGFR-mutant (ADAURA), alectinib if ALK-positive (ALINA); adjuvant chemotherapy otherwise for stage II+. | 89 | ||
| EGFR | Early stage | Surgery or SBRT; perioperative chemo-immunotherapy; adjuvant osimertinib (EGFR) or alectinib (ALK). | NCCN Guidelines: Non-Small Cell Lung Cancer | 87 |
Locally advanced
| Subgroup | Setting | Approach | Products and trials | Guideline | Evidence |
|---|---|---|---|---|---|
| All comers | Stage III unresectable | Concurrent platinum chemoradiation → durvalumab 1 year (PACIFIC), or osimertinib until progression if EGFR-mutant (LAURA). Proton therapy in selected cases. | 91 | ||
| EGFR | Stage III unresectable | Chemoradiation → durvalumab (PACIFIC) or osimertinib (LAURA, EGFR). | NCCN Guidelines: Non-Small Cell Lung Cancer | 91 |
Advanced, first line
| Subgroup | Setting | Approach | Products and trials | Guideline | Evidence |
|---|---|---|---|---|---|
| All comers | Metastatic, driver-negative | PD-(L)1 ± chemotherapy; docetaxel or ADC/TTFields second line. | NCCN Guidelines: Non-Small Cell Lung Cancer | 98 | |
| All comers | Metastatic, squamous | Pembrolizumab + carboplatin + (nab-)paclitaxel (KEYNOTE-407); no ADC approved (TROPION-Lung01 showed no benefit in squamous); ivonescimab + chemotherapy under study (HARMONi-3). | 98 | ||
| ALK | Metastatic, ALK-rearranged | Lorlatinib (CROWN; 5-year PFS 60%) or alectinib first line; on progression, neladalkib (under review) or lorlatinib if not used; local therapy for oligoprogression; chemotherapy. | 86 | ||
| BRAF | Metastatic, BRAF V600E | Dabrafenib + trametinib or encorafenib + binimetinib first line; chemo-IO as alternative. | 87 | ||
| EGFR | Metastatic, EGFR exon 19 del / L858R | First line: osimertinib ± platinum-pemetrexed (FLAURA2) or amivantamab + lazertinib (MARIPOSA, OS benefit). Progression: re-biopsy/ctDNA; amivantamab + chemotherapy (MARIPOSA-2), Dato-DXd (TROPION-Lung05), platinum doublet; MET TKI add-on if MET-amplified; platinum-etoposide if small-cell transformation. | 88 | ||
| EGFR exon 20 | Metastatic, EGFR exon 20 insertion | Amivantamab + platinum-pemetrexed (PAPILLON); sunvozertinib later line. | 79 | ||
| HER2 | Metastatic, HER2-mutant | First line: zongertinib (2026) or chemo-IO; sevabertinib (Nov 2025) or T-DXd after prior therapy. | 97 | ||
| HR-positive | Metastatic, driver-positive | Matched TKI or bispecific; ADCs after progression. | ESMO-MCBS · 3 (DESTINY-Lung02, HER2-mutant, second line) | 87 | |
| KRAS G12C | Metastatic, KRAS G12C | First line: PD-(L)1 ± chemotherapy by PD-L1 (G12C inhibitor + IO combinations in phase 3: olomorasib SUNRAY-01, divarasib Krascendo 2). Second line: sotorasib or adagrasib (CodeBreaK 200, KRYSTAL-12); divarasib superior head-to-head (Krascendo 1, 2026). | 89 | ||
| MET | Metastatic, MET exon 14 skipping | Capmatinib or tepotinib first line; telisotuzumab vedotin for c-Met-overexpressing EGFR-wild-type disease after chemotherapy (accelerated 2025). | 61 | ||
| NTRK | Metastatic, NTRK-fusion | Larotrectinib, entrectinib, or repotrectinib (tumour-agnostic). | 43 | ||
| PD-L1 | Metastatic, driver-negative, PD-L1 TPS ≥50% | Pembrolizumab (KEYNOTE-024) or cemiplimab monotherapy; add chemotherapy for high burden or rapid progression. Ivonescimab beat pembrolizumab in China (HARMONi-2); not approved in the US. | 98 | ||
| PD-L1 | Metastatic, driver-negative, PD-L1 TPS <50% | Pembrolizumab + platinum doublet (KEYNOTE-189 non-squamous; KEYNOTE-407 squamous); nivolumab + ipilimumab ± chemotherapy; tremelimumab + durvalumab + chemotherapy for PD-L1-negative or STK11/KEAP1-altered disease. Second line: docetaxel ± ramucirumab, TTFields, or trials of ADCs. | 98 | ||
| RET | Metastatic, RET-fusion | Selpercatinib first line (LIBRETTO-431); pralsetinib alternative. | 86 | ||
| ROS1 | Metastatic, ROS1-rearranged | Repotrectinib or zidesamtinib (2026) first line; entrectinib/crizotinib alternatives. | 43 |
Sequence and caution pairings
SequenceApproved
EGFR TKI → ADC on progression
After the lung cancer pill stops working, an ADC that does not care which resistance mutation emerged.
SequenceStandard of care
Sequence: targeted therapy before immunotherapy in driver-positive NSCLC
If a lung cancer has a targetable mutation, give the pill first; immunotherapy works poorly in these tumours and raises the risk of severe side effects when a pill follows.
CautionApproved
Caution: DXd ADC + agents with pneumonitis risk
Enhertu and its DXd cousins can inflame the lungs; combining them with immunotherapy, radiation, or mTOR inhibitors stacks that risk.
Caution
Caution: TIGIT + PD-(L)1 blockade
Adding a TIGIT blocker to PD-1/PD-L1 blockade looked good in phase 2 and then failed repeatedly in phase 3.
Regimens in the library
Trastuzumab deruxtecan 5.4 mg/kgPembrolizumab + pemetrexed + platinumPembrolizumab + carboplatin + paclitaxelNivolumab + ipilimumab + 2 cycles of platinum doubletOsimertinibCisplatin + vinorelbine (adjuvant)Chemoradiation then durvalumab (PACIFIC)Cisplatin + etoposide (EP)Cisplatin + pemetrexedCarboplatin + paclitaxelPembrolizumab monotherapyDabrafenib + trametinib
Lines and subgroups are parsed from the setting text of each standard-of-care row and can misclassify an unusual phrasing; the row’s own setting is always shown. Guideline chips reflect the NCCN category and ESMO-MCBS grade recorded on the cancer page, checked on its stated date. Not medical advice.