Non-Small Cell Lung Cancer (NSCLC)

Background:

• NSCLC (85%):

  • Adenocarcinoma (~60%)

  • Squamous (~25%)

  • Large cell carcinoma and other less common histologies (~15%)

• SCLC (15%)

Staging:

• Recommend to memorize TNM staging (questions will not always state what stage but may provide size, nodal involvement, etc)

  • T:

    • High-yield size cutoffs: T2 begins at 3 cm

    • Each T goes up by 2 cm: T2 (3 cm) → T3 (5cm) → T4 (7cm)

  • N1:

    • Ipsilateral peribronchial

    • Ipsilateral hilar

    • Intrapulmonary LN

  • N2:

    • Ipsilateral mediastinal

    • Subcarinal LN

  • N3:

    • Contralateral hilar

    • Contralateral mediastinal

    • Scalene LN

    • Supraclavicular LN

Treatment:

Stage IB-IIIA require biomarker testing: EGFR (particularly exon 19 del/L858R), ALK, RET, PD-L1

Stage I:

• Curative intent:

  • Surgical resection (preferred)

    • If positive margins: 

      • Re-resection

      • Postoperative radiation if re-resection is not feasible

    • If negative margins:

      • Surveillance

  • Definitive radiation (if inoperable)

• Stage IA: 

  • No routine adjuvant chemotherapy.

• Stage IB: 

  • Consider adjuvant chemotherapy ONLY in selected high-risk patients.

    • High risk features:

      • Poorly differentiated tumors, lymphovascular invasion, wedge resection, visceral pleural involvement, unknown LN status. 

    • Surgery → adjuvant chemo

      • Regimens:

        • Platinum/Taxol x4

        • Platinum/Pemetrexed x4 (nonsquamous only)

    • Surgery → adjuvant chemo → adjuvant osimertinib x3 years if EGFR Exon 19 del/L858R (ADAURA)

    • Surgery → adjuvant chemo → adjuvant alectinib if ALK mutated (ALINA)

    • Surgery → adjuvant chemo → adjuvant IO

      • Atezolizumab x1 year if PD-L1% or higher (IMPower-010)

      • Pembrolizumab x1 year regardless of PDL-1 (Keynote-091/PEARLS)

Stage II:

• Surgery → adjuvant chemo

  • Regimens:

    • Platinum/Taxol x4

    • Platinum/Pemetrexed x4 (nonsquamous only)

• Surgery → adjuvant chemo → adjuvant osimertinib x3 years if EGFR Exon 19 del/L858R (ADAURA)

• Surgery → adjuvant chemo → adjuvant alectinib if ALK mutated (ALINA)

• Surgery → adjuvant chemo → adjuvant IO

  • Atezolizumab x1 year if PD-L1% or higher (IMPower-010)

  • Pembrolizumab x1 year regardless of PDL-1 (Keynote-091/PEARLS)

Stage III:

Treatment with curative intent even if it is unresectable.

• If resectable: 

  • Neoadjuvant therapy → Surgery

    • Neoadjuvant options:

      • Chemotherapy

      • Concurrent chemo-RT

      • Chemo-IO (preferred)

        • Chemo+Nivolumab x3 cycles → surgery (Checkmate 816)

        • Chemo+Nivolumab x3 cycles → surgery → adjuvant nivolumab (NADIM)

        • Chemo+Pembrolizumab x4 cycles → surgery → adjuvant pembrolizumab (Keynote-671)

        • Chemo+Durvalumab ×4 cycles → surgery → adjuvant durvalumab (AEGEAN)

  • Surgery → Adjuvant therapy

    • Surgery → adjuvant chemo

      • Regimens:

        • Platinum/Taxol x4

        • Platinum/Pemetrexed x4 (nonsquamous only)

    • Surgery → adjuvant chemo → adjuvant osimertinib x3 years if EGFR Exon 19 del/L858R (ADAURA)

    • Surgery → adjuvant chemo → adjuvant alectinib if ALK mutated (ALINA)

    • Surgery → adjuvant chemo → adjuvant IO

      • Atezolizumab x1 year if PD-L1% or higher (IMPower-010)

      • Pembrolizumab x1 year regardless of PDL-1 (Keynote-091/PEARLS)

• If unresectable:

  • Definitive concurrent chemo-RT → (if no progression of disease) consolidation based on EGFR exon 19 del/L858R status

    • Regimens:

      • Platinum/Taxol x4

      • Platinum/Pemetrexed x4 (nonsquamous only)

    • Consolidation If EGFR+:

      • Consolidation Osimertinib 80 mg PO once daily until progression or toxicity (LAURA)

        • PFS 39.1 months with osimertinib vs 5.6 months with placebo

    • Consolidation If EGFR-:

      • Consolidation durvalumab for up to 12 months (PACIFIC)

        • PFS 16.8 months with Durvalumab vs 5.6 months with placebo

Stage IV:

• NGS: check for driver mutations and PD-L1 TPS, EGFR (20-25%), ALK (5-7%), ROS1, RET, MET, BRAF V600E, KRAS G12C (13%), HER2 (ERBB2)

  • If waiting for NGS, can start with chemo backbone and add in IO during C2

• Chemo + IO:

  • Indications:

    • No driver mutations

    • Large burden of disease

    • End organ damage/visceral crisis

  • Regimen:

    • Platinum/Taxol + Pembrolizumab (Keynote-407)

      • Addition of pembrolizumab resulted in significantly longer OS and PFS than chemotherapy alone. 

    • Platinum/Pemetrexed (nonsquamous only) + Pembrolizumab (Keynote-189)

  • The survival benefit for chemo+IO was observed across all categories of PD-L1 expression.

• Pembrolizumab:

  • Pembrolizumab monotherapy can be used if high PD-L1 >50% (Keynote-024) and can be extended as first-line therapy even with low PDL-1 TPS (1-49%) (Keynote-042)

• Second Line agents:

  • EGFR Exon19 del/L858R: 

    • Osimertinib (FLAURA)

    • Osimertinib + chemo (FLAURA-2)

    • Amivantamab + Lazertinib

    • Afatinib

    • Dacomitinib

    • Erlotinib +/- Bev

    • Erlotinib +/- Ramicurumab

    • Gefitinib

  • EGFR Exon 20 insertion mutation:

    • Amivantamab (CHRYSALIS)

    • Amivantamab + chemo (PAPILLON)

  • ALK fusion 5-7%:

    • Can pre-screen with ALK IHC and confirm with FISH or PCR

    • ALK TK inhibitors (Alectinib, Brigatinib, Crizontinib, Lorlatinib) are category 1 for first line therapy. They are superior to chemo in 1L and 2L setting

      • 1G ALK TKI: Crizotinib

      • 2G ALK TKI: Ceritinib, Alectinib, Brigatinib, Ensartinib

      • 3G ALK TKI: Lorlatinib (CROWN trial)

      • 4G ALK TKI: NVL-655

  • RET fusion: 

    • Selpercatinib

  • ROS1 fusion: 

    • Repotrectinib, Entrectinib, Crizontinib, Lorlatinib

  • KRAS G12C:

    • Sotorasib, Adagrasib

      • Both approved for 2L after 1+ systemic therapy

  • MET Exon 14 Skipping Mutation:

    • Capmatinib, Crizotinib, Tepotinib

  • BRAF V600E:

    • Dabrafenib/Trametinib

  • HER2:

    • Fam-trastuzumab deruxtecan (Enhertu)

  • NTRK

    • Repotrectinib

    • Larotrectinib

    • Entrectinib

  • Nivolumab

  • Atezolizumab

  • Docetaxel + Ramucirumab/Pemetrexed/Gemcitabine/Abraxane/Vinorelbine

  • Enhertu

  • Telisotuzumab (cMET/MET >/= 50% IHC 3+ and EGFR wild type)

  • Datopotamab deruxtecan: Trop-2 directed ADC (TROPION-Lung-01)

    • EGFR exon 19 del/L858R