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Metastatic non-small cell lung cancer — molecular therapy and immunotherapy
In metastatic lung cancer you first look for a driver mutation with NGS; if there is one — targeted therapy, and if not — immunotherapy guided by PD-L1, alone or with chemotherapy.
Why it matters in the exam
Questions on metastatic lung cancer are among the most frequent in the oncology bank. The candidate gets a never-smoker with adenocarcinoma, an NGS report and a PD-L1 level, and must choose first-line therapy, name a resistance mechanism or recognise a side effect. Details are also asked, such as the meaning of TPS staining with the 22C3 antibody, the advantage of alectinib over crizotinib, the meaning of a MET exon 14 mutation, and premedication for pemetrexed with folic acid and vitamin B12. Recurring questions also cover liquid biopsy, brain metastases in a patient with a driver mutation, and what to do when a single site progresses while the rest of the disease is controlled — usually continue the drug and irradiate that site.
Read the NGS report to the end before choosing an answer.
Key points
- Every metastatic adenocarcinoma, and most squamous tumours in never-smokers, is tested by NGS before treatment.
- A driver mutation is treated with a targeted drug first line, regardless of PD-L1.
- Without a driver: PD-L1 of 50% or more — pembrolizumab; below 50% — chemotherapy with immunotherapy.
- Pemetrexed only in non-squamous disease, with folic acid and vitamin B12 beforehand.
- On progression under targeted therapy, re-biopsy to identify the resistance mechanism.
Summary table
| Finding | First-line treatment | Resistance or note |
|---|---|---|
| EGFR exon 19 or L858R | Osimertinib (possibly with chemotherapy), or amivantamab with lazertinib | Resistance: C797S, MET amplification, transformation to small cell |
| ALK fusion | Alectinib, brigatinib or lorlatinib | Good brain penetration; alectinib beats crizotinib in progression-free survival and brain protection |
| ROS1, RET, NTRK, BRAF V600E, MET exon 14 | The matching targeted inhibitor for each alteration | MET exon 14: skipping the exon prevents receptor degradation and increases signalling |
| KRAS G12C | Chemo-immunotherapy first line; sotorasib or adagrasib second line | The mutation is common in smokers |
| No driver, PD-L1 of 50% or more | Pembrolizumab alone (or with chemotherapy) | TPS = percentage of tumour cells that stain |
| No driver, PD-L1 below 50% | Platinum-based chemotherapy with pembrolizumab | Pemetrexed only in non-squamous; in squamous — paclitaxel or nab-paclitaxel |
| EGFR exon 20 insertion | Amivantamab with platinum-based chemotherapy | Standard-dose osimertinib barely works in this mutation, so it matters to spot it in the NGS report |
Free exam questions
בת 65, סובלת מ- squamous cell carcinoma של הריאה וגרורות בכבד, טופלה ב carboplatin+ gemcitabine במשך 4 חודשים וכעת מחלתה התקדמה. בבדיקות מולקולריות ללא מוטציות DRIVER ו PDL1 שלילי (קטן מ 1%). איזה טיפול עשוי להאריך את ההישרדות שלה? (the question as examined, in Hebrew)
- א. הוספת Ramucirumab ל docetaxel
- ב. טיפול ב Ninolumab+Ipilimumab
- ג. טיפול ב Atezolizumab
- ד. טיפול ב Pembrolizumab
בסרטן ריאה, למה גורמת מוטציה של MET הממוקמת באקסון 14 ? (the question as examined, in Hebrew)
- א. מניעת פרוק החלבון
- ב. שפעול האתר הפעיל של החלבון
- ג. חיבור rearrangement עם פרטנר משפ על
- ד. פעילות יתר של הליגנד
מה מבין הבאים הוא הטיפול המתאים ביותר בקו הראשון למרבית סרטני הריאה בהם נמצא insertion באקסון 20 ? (the question as examined, in Hebrew)
- א. Erlotinib
- ב. Gefitinib
- ג. Pembrolizumab
- ד. Carboplatin and paclitaxel
In the full version for subscribers
- A simple algorithm
- Memory aid
- Exam traps
- 5 review cards
- Enough for IMLE
The full version is open to subscribers of: Oncology, Medical licensing exam (IMLE), Internal medicine.
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Sources
- NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer, 2026 — Systemic therapy for advanced or metastatic disease
- ESMO Clinical Practice Guideline: Oncogene-addicted metastatic NSCLC, 2023 — Diagnosis, treatment and follow-up
- ESMO Clinical Practice Guideline: Non-oncogene-addicted metastatic NSCLC, 2023 — Diagnosis, treatment and follow-up
Sources are given for further reading; the text is written afresh and not copied from them.
Reviewed by the Examqo AI Professor · 2026-11-06. The text may contain errors; when in doubt, check the source.