OpenOnco Handbook

Metastatic NSCLC: driver-first treatment reasoning

draft hcp_learner en

Deterministic learning chapter over OpenOnco KB entities, synthetic cases, and source records.

Learning objectives

  1. Explain why metastatic NSCLC first-line reasoning starts with actionable driver testing before PD-L1-only decisions.
  2. Distinguish EGFR, ALK, ROS1, MET exon 14, RET, BRAF V600E, and NTRK driver branches from driver-negative immunotherapy branches.
  3. Recognize PD-L1 TPS as a treatment-stratifying marker only after actionable drivers are excluded or addressed.

At a glance

  • Comprehensive molecular testing is the central first-line gate in metastatic NSCLC.
  • Actionable drivers route to targeted therapy branches before PD-L1 immunotherapy branches.
  • PD-L1 TPS still matters, but mainly in the driver-negative pathway.
  • Brain metastases, frailty, organ dysfunction, and urgent complications remain parallel MDT concerns.
  • The chapter is OpenOnco-authored educational content, not official ESMO or CME material.

Driver-first cascade

The metastatic NSCLC chapter emphasizes driver-first routing. EGFR, ALK, ROS1, MET exon 14, RET, BRAF V600E, and NTRK are evaluated before the driver-negative PD-L1 immunotherapy pathway.

Linked entities

ALGO-NSCLC-METASTATIC-1LALGO-NSCLC-METASTATIC-1LalgorithmsRF-NSCLC-HIGH-RISK-BIOLOGYActionable molecular driver detected (EGFR / ALK / ROS1 / KRAS G12C / BRAF V600E / MET ex14 / RET / NTRK / HER2 mut) — driver-targeted TKI / ADC takes precedence over ICI ± chemo regardless of PD-L1 TPS.redflagsTEST-NGS-COMPREHENSIVEComprehensive NGS tumor panel (DNA + RNA, ≥300 genes)tests

Section sources

  • SRC-NCCN-NSCLC-2025 NCCN Clinical Practice Guidelines — Non-Small Cell Lung Cancer
  • SRC-ESMO-NSCLC-METASTATIC-2024 ESMO Clinical Practice Guideline on Metastatic Non-Small Cell Lung Cancer

EGFR branch

Classical sensitizing EGFR alterations route to the EGFR first-line branch in the OpenOnco model. PD-L1 expression should not be used to skip driver-directed reasoning.

Linked entities

BIO-EGFR-MUTATIONEGFR mutation status (NSCLC actionable)biomarkersIND-NSCLC-EGFR-MUT-MET-1LIND-NSCLC-EGFR-MUT-MET-1LindicationsREG-OSIMERTINIB-NSCLCOsimertinib monotherapy (EGFR-mut NSCLC, 1L metastatic OR adjuvant)regimens

Section sources

  • SRC-FLAURA-SORIA-2018 Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer
  • SRC-NCCN-NSCLC-2025 NCCN Clinical Practice Guidelines — Non-Small Cell Lung Cancer

Driver-negative pathway

When no actionable driver is found, PD-L1 TPS helps separate pembrolizumab monotherapy from chemo-immunotherapy strategies. Frailty, organ dysfunction, and urgent thoracic complications remain safety gates.

Linked entities

BIO-PDL1-TPSPD-L1 Tumor Proportion Score (TPS)biomarkersRF-NSCLC-PDL1-50-PLUSMetastatic NSCLC with PD-L1 tumor proportion score (TPS) ≥50% by 22C3 IHC, no actionable driver mutations (EGFR/ALK/ROS1/BRAF/RET/MET/NTRK/ KRAS-G12C/HER2 wild-type or unselected). KEYNOTE-024 (Reck NEJM 2016; 5-year update Reck JCO 2021) established pembrolizumab monotherapy 1L over platinum-doublet chemo for TPS ≥50% (mOS 26.3 vs 13.4 mo, 5y OS 31.9% vs 16.3%). FDA-approved 2016. Atezolizumab (IMpower-110) and cemiplimab (EMPOWER-Lung-1) similarly approved. ESMO/NCCN 2024 prefer pembrolizumab monotherapy 1L for TPS ≥50% over chemo + IO combinations (KEYNOTE-189 / -407) when patient is fit and the TPS-50% determination is reliable. redflagsIND-NSCLC-PDL1-HIGH-MET-1LIND-NSCLC-PDL1-HIGH-MET-1LindicationsIND-NSCLC-PDL1-LOW-NONSQ-MET-1LIND-NSCLC-PDL1-LOW-NONSQ-MET-1Lindications

Section sources

  • SRC-KEYNOTE-024-RECK-2016 Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer
  • SRC-KEYNOTE-189-GANDHI-2018 Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer

Worked synthetic cases

  • patient_nsclc_egfr_ex19del_1l_osimertinib EGFR exon 19 deletion metastatic NSCLC - driver-first routing, EGFR-targeted branch examples/patient_nsclc_egfr_ex19del_1l_osimertinib.json
  • patient_nsclc_pdl1_high_pembro_mono Driver-negative PD-L1 high metastatic NSCLC - PD-L1 high branch, driver-negative assumption examples/patient_nsclc_pdl1_high_pembro_mono.json

Practice questions

0 of 3 answered · 0 correct

Answers, score, and reasoning tags are kept in your browser session only and clear when you close this tab. Multi-select questions require every correct option (and no extras) for a credit.

Question 1 type_a intro HQ-NSCLC-MET-1L-001

In metastatic NSCLC, what is the first major routing concept in the OpenOnco handbook chapter?

Question 2 type_a intermediate HQ-NSCLC-MET-1L-002

A metastatic NSCLC case has an EGFR exon 19 deletion. In this learning model, which branch should be considered before PD-L1 monotherapy?

Question 3 type_k intermediate HQ-NSCLC-MET-1L-003

Which statements are true for the OpenOnco metastatic NSCLC first-line chapter?