Lung Cancer

Non-Small Cell Lung Cancer (NSCLC)

Background:

• NSCLC (85%): Adenocarcinoma (60%), Squamous (30-35%), other Neuroendocrine (5%)

• SCLC (15%)

Staging:

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

  • T2 starts at 3 cm and each T goes up by 2 cm → T2 (3 cm), T3 (5cm), T4 (7cm)

  • N1 is hilar nodes, N2 is ipsilateral mediastinal nodes, N3 is contralateral OR supraclavicular nodes

Stage I NSCLC

• Curative intent: Surgical resection (preferred) or radiation (if inoperable)

  • If positive margins, consider RT or re-resection

• Typically no adjuvant chemotherapy for stage I

• Stage IB:

  • Obtain NGS for Stage IB (T2 and up) and above

  • Adjuvant osimertinib if EGFR exon 19 deletion or L858R (ADAURA)

  • Adjuvant Alectinib if ALK mutated (ALINA)

Stage II NSCLC

• Curative intent: Surgical resection or radiation (if unresectable)

• Can give adjuvant chemotherapy for stage IIA with high risk features and stage IIB

  • High-risk features: poorly differentiated tumors, lymphovascular invasion, wedge resection, visceral pleural involvement, and unknown lymph node status. 

  • Regimens:

    • Platinum/Taxol x4

    • Platinum/Pemetrexed x4

• Adjuvant immunotherapy after chemotherapy (if tumor above 4cm)

  • If EGFR+: No adjuvant IO (concern for pneumonitis)

  • Options for adjuvant IO:

    • Atezolizumab x1 year for Stage II-IIIA with PD-L1% or higher (IMPower-010)

    • Pembrolizumab x1 year for stage IB-IIIA regardless of PDL-1 (Keynote-091)

• Adjuvant osimertinib x3 years if EGFR Exon 19 deletion or L858R

  • ADAURA Trial: Stage II-IIIA EGFR-mutated NSCLC after complete tumor resection randomized to adjuvant osimertinib 80 mg daily vs placebo until disease recurrence

    • At 2-years: DFS was 90% (osimertinib) vs 44% (placebo). OS was 98% (osimertinib) vs. 85% (placebo).

    • At 5 years: OS was 85% (osimertinib) vs. 73% (placebo).

• Adjuvant alectinib if ALK mutated in resected stage IB-IIIA (ALINA)

Stage III NSCLC

• Curative intent: Surgical resection or radiation (if unresectable)

• Adjuvant chemotherapy

  • Platinum/Taxol x4

  • Platinum/Pemetrexed x4

• Adjuvant immunotherapy after chemotherapy

  • No adjuvant IO if EGFR+

  • Atezolizumab x1 year if PD-L1 1% or higher (IMPower-010)

  • Pembrolizumab x1 year regardless of PD-L1 (Keynote-091)

• Adjuvant Osimertinib x3 years if EGFR Exon 19 deletion or L858R (ADAURA)

• Adjuvant Alectinib if ALK mutated in resected stage IB-IIIA (ALINA)

• If residual disease:

  • R1 (microscopic disease): Sequential or concurrent chemoRT

  • R2 (macroscopic disease): Concurrent chemoRT

• If unresectable:

  • Concurrent chemo-RT followed by consolidation Durvalumab x1 year

    • PACIFIC trial → PFS was 16.8 months (Durvalumab) vs 5 months (placebo). OS was 83% 1 year and 63% 2 years.

  • If EGFR+: chemo-RT + djuvant Osimertinib 80 mg PO once daily until progression

    • LAURA Trial → PFS significantly improved (39.1 mo with osimertinib vs 5.6 mo with placebo)

• If resectable: Neoadjuvant therapies:

  • Nivolumab + chemo x3 cycles → surgery → adjuvant chemo (no adjuvant IO)

    • Checkmate 816: median event free survival 31.6 months Vs 20.8 months (chemo alone). pCR rate was 24% vs 2.2% (chemo alone).

  • Nivolumab + chemo x3 cycles → surgery → adjuvant nivo (if R0) x6 months (NADIM)

  • Pembro + chemo→ surgery → Adjuvant Pembro (Keynote-671)

  • Durvalumab + chemo → surgery → Adjuvant Durvalumab (AEGEAN)

Stage IV NSCLC 

• 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 (if no driver mutations): Consider if large burden of disease or end organ damage/visceral crisis

  • Carboplatin + Pemetrexed + Pembrolizumab

    • Keynote-189: Platinum + Pemetrexed + Pembrolizumab vs no pembro in adenocarcinomas. The survival benefit for pembrolizumab + chemo was observed across all categories of PD-L1 expression.

  • Carboplatin + Taxol + Pembrolizumab

    • Keynote-407: Platinum + Taxol + Pembrolizumab vs no pembro in SCC. The survival benefit for pembrolizumab + chemo was observed across all categories of PD-L1 expression. The addition of pembrolizumab resulted in significantly longer OS and PFS than chemotherapy alone. 

• Pembrolizumab monotherapy

  • Keynote-024: Pembrolizumab monotherapy can be used if PD-L1 >50%. 

  • Keynote-042: Pembrolizumab monotherapy can be extended as first-line therapy even with low PDL-1 TPS (1-49%). 

• Other second line agents:

  • 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 or L858R

• Targeted therapies:

  • EGFR Exon 21 L858R or Exon del 19: 

    • 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

      
      

Small Cell Lung Cancer (SCLC)

Background: 

• Poor prognosis. Median OS ~ 12-14 month

• Limited-Stage SCLC: confined to the ipsilateral hemithorax, which can be safely encompassed within a radiation field

• Extensive-Stage SCLC: metastatic, beyond the ipsilateral hemithorax, including malignant pleural or pericardial effusion

• May present with SVC Syndrome

  • IR consult - Ideally could still get tissue diagnosis before treating

  • Rad Onc consult for Emergent treatment with concurrent chemoRT

LS-SCLC Treatment

• Stage I-IIA (T1-2 only): lobectomy + adjuvant chemotherapy (Cisplatin and etoposide)

• Stage IIB-III: Concurrent chemo-RT

  • Consider post-chemo-RT consolidation Durvalumab (ADRIATIC) → OS was 55.9 months (durvalumab) vs 33.4 months (placebo). PFS was 16.6 months (durvalumab) vs 9.2 months (placebo).

• Consider prophylactic cranial irradiation (decreases brain metastases and increases OS)

ES-SCLC Treatment

• No radiation or surgery

• Consider MRI brain

• Combination chemo+ IO (IMPOWER-133, CASPIAN)

  • (carboplatin/cisplatin + etoposide x4 cycles) + (Atezolizumab/Durvalumab)

• For brain metastases: start with WBRT + steroids

Relapsed SCLC Treatment

• Consider if platinum-resistant. Can re-challenge with Carboplatin + etoposide if relapse > 6 months after platinum exposure

• Lurbinectedin and Topotecan can be used in 2nd line if relapse < 6 months (chemo-refractory)

• Talratamab: bispecific Ab (DeLLphi-301)

• Clinical Trial

  
  

Mesothelioma

Background: 

• Types:

  • Epithelioid Mesothelioma: better prognosis

  • Non-Epithelioid Mesothelioma (Sarcomatoid or Biphasic)

• Highly aggressive cancer, typically unresectable at diagnosis. 

• Less than 10% of patients survive 5 years or beyond. 

Treatment:

• Ipilimumab + Nivolumab (Checkmate-743): prefered for sarcomatoid

• Chemo:

  • Cisplatin + Pemetrexed,

  • Cisplatin + Pemetrexed + Bevacizumab

• Second line: 

  • If immunotherapy used in first line: use chemo

  • If chemo used in first line: use ipi/nivo