Metastatic NSCLC with PD-L1 tumor proportion score (TPS) ≥50% by 22C3 IHC, no actionable...

Deterministic view of the source YAML entity. Clinical authority remains with the cited source IDs and reviewer sign-off state.

ID	`RF-NSCLC-PDL1-50-PLUS`
Type	Red flag
Status	reviewed 2026-04-27 \| pending_clinical_signoff
Diseases	`DIS-NSCLC`
Sources	`SRC-ESMO-NSCLC-METASTATIC-2024` `SRC-KEYNOTE-024-RECK-2016` `SRC-NCCN-NSCLC-2025`

Red Flag Origin

Definition	Metastatic 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.
Clinical direction	intensify
Category	high-risk-biology
Shifts algorithm	ALGO-NSCLC-METASTATIC-1L

Trigger Logic

{
  "all_of": [
    {
      "any_of": [
        {
          "comparator": ">=",
          "finding": "pdl1_tps",
          "threshold": 50
        },
        {
          "comparator": ">=",
          "finding": "pdl1_tps_22c3",
          "threshold": 50
        },
        {
          "comparator": ">=",
          "finding": "BIO-PDL1-TPS",
          "threshold": 50
        }
      ]
    },
    {
      "any_of": [
        {
          "finding": "egfr_mutation",
          "value": false
        },
        {
          "finding": "egfr_mutation",
          "value": "negative"
        },
        {
          "finding": "actionable_driver_mutation",
          "value": false
        }
      ]
    },
    {
      "any_of": [
        {
          "finding": "alk_fusion",
          "value": false
        },
        {
          "finding": "alk_status",
          "value": "negative"
        }
      ]
    }
  ],
  "type": "biomarker"
}

Notes

TPS-50% bypass of chemo applies only AFTER all driver mutations are excluded (EGFR, ALK, ROS1, BRAF V600E, MET ex14, RET, NTRK, KRAS G12C, HER2 — at minimum the SOC panel). EGFR-mutant or ALK-rearranged disease responds POORLY to ICI even at TPS-100% — driver-targeting TKI is always the correct 1L. TPS 1-49% — chemo + ICI combo (KEYNOTE-189 non-squamous, KEYNOTE-407 squamous) preferred; pembrolizumab monotherapy is still an option (KEYNOTE-042) but inferior to combo. TPS <1% — chemo + ICI combo or chemo + ipi/nivo (CheckMate-9LA); monotherapy not recommended. STK11/KEAP1 co-mutation is a negative predictor for ICI response even at high TPS — emerging biomarker for chemo + ICI combo over monotherapy. Detection: 22C3 IHC central laboratory preferred; SP263 (used in IMpower studies) and 22C3 are NOT interchangeable for the 50% cutoff (Blueprint comparison). Brain metastases are NOT a contraindication if asymptomatic and ≤2 cm — KEYNOTE-024 included controlled brain mets.

Used By

Algorithms

ALGO-NSCLC-ADJUVANT - ALGO-NSCLC-ADJUVANT
ALGO-NSCLC-METASTATIC-1L - ALGO-NSCLC-METASTATIC-1L

Red flag

RF-PAN-PDL1-CLONE-22C3-PEMBRO-ELIGIBLE - PD-L1 IHC result generated using the Dako 22C3 pharmDx clone — the FDA-approved companion...