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Genomics

Non-Small Cell Lung Cancer

Edward S. Kim, MD, MBA, FACP, FASCO; Jennifer Benbow, PhD, CCRP 
Reviewed on June 28, 2024
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Introduction

  • Virtual Molecular Tumor Board
  • Patient: Non-small cell lung cancer
  • Carolinas HealthCare System/Levine Cancer Institute
  • Presented by: Dr. Kathryn Mileham

Initial Diagnosis

A 68-year-old female never smoker developed cough that led to a CXR which was without notable abnormality in 2007. Due to lack of resolving symptoms, she underwent additional imaging.

  • 9/17/07: CT chest identified a lobulated right central mass (3.2 x 3.3 cm)
  • 9/26/07: PET/CT confirmed the right upper lobe mass (3.3 x 2.9 cm; mSUV 9.3) and adjacent superior hilar mass (2.5 x 2.2 cm; mSUV 8.0)
  • 10/4/07: Needle core biopsy of RUL mass was pathologically consistent with TTF-1 positive, moderately differentiated adenocarcinoma
  • 11/5/07: Bronchoscopy and mediastinal lymph node biopsy was also pathologically consistent with TTF-1 positive adenocarcinoma
  • T2a N2 M0 stage IIIA non-small cell lung cancer was diagnosed

Treatment History

  • 11/20/07 – 1/30/08: Concurrent chemoradiation with four cycles of cisplatin-navelbine
  • 3/11/08…

Introduction

  • Virtual Molecular Tumor Board
  • Patient: Non-small cell lung cancer
  • Carolinas HealthCare System/Levine Cancer Institute
  • Presented by: Dr. Kathryn Mileham

Initial Diagnosis

A 68-year-old female never smoker developed cough that led to a CXR which was without notable abnormality in 2007. Due to lack of resolving symptoms, she underwent additional imaging.

  • 9/17/07: CT chest identified a lobulated right central mass (3.2 x 3.3 cm)
  • 9/26/07: PET/CT confirmed the right upper lobe mass (3.3 x 2.9 cm; mSUV 9.3) and adjacent superior hilar mass (2.5 x 2.2 cm; mSUV 8.0)
  • 10/4/07: Needle core biopsy of RUL mass was pathologically consistent with TTF-1 positive, moderately differentiated adenocarcinoma
  • 11/5/07: Bronchoscopy and mediastinal lymph node biopsy was also pathologically consistent with TTF-1 positive adenocarcinoma
  • T2a N2 M0 stage IIIA non-small cell lung cancer was diagnosed

Treatment History

  • 11/20/07 – 1/30/08: Concurrent chemoradiation with four cycles of cisplatin-navelbine
  • 3/11/08: PET/CT with good response, no new disease
  • 9/15/09: Surveillance CT imaging suggested recurrence and PET/CT indicated new right posterior medial lower lobe lung nodule (0.9 x 1.0 cm; not metabolically active), right diaphragmatic lesion (1.3 x 1.5 cm; mSUV 2.8), and bone metastases
  • 10/1/09: New biopsy was pathologically consistent with adenocarcinoma of the lung and molecular testing was positive for EGFR L858R (sensitizing mutation)
  • 11/19/09: Erlotinib 150mg/day
  • 11/2/11: Disease progression in lung, stable bone metastases, no metastases below the diaphragm
  • 2/1/12: New biopsy was pathologically consistent with adenocarcinoma of the lung and molecular testing was positive for EGFR L858R (sensitizing) and EGFR T790M (resistant)
  • 3/1/12: Enrolled and treated on clinical trial (THO-09103) with single agent afatinib 40mg/day
  • 9/13/12: Disease progression in the lung, so was crossed over to afatinib 40mg/day plus cetuximab 500 mg/m2 IV Q2W
  • 10/12/15: Disease progression in lung, stable bone metastases, no metastases below the diaphragm
  • 11/11/15 and 11/19/15: Cetuximab and afatinib were discontinued, respectively
  • 11/2/2015: Cell-free DNA from the blood had been evaluated for genomic alterations; EGFR L858R and T790M mutations were both identified
  • 11/20/15: Osimertinib 80 mg/day
  • 6/13/16: Disease progression in lung, stable bone metastases, no metastases below the diaphragm
  • 6/20/16: New biopsy was pathologically consistent with adenocarcinoma of the lung and molecular testing was positive for EGFR L858R (sensitizing) and negative for EGFR T790M and was without small cell transformation
  • 7/14/16: Erlotinib 100 mg/day
  • 8/6/16: Disease progression in lung, stable bone metastases, no metastases below the diaphragm

Imaging

Enlarge  Figure 1-1: 9/15/09: new metastatic EGFR L858R mutated NSCLC, treated with erlotinib
Figure 1-1: 9/15/09: new metastatic EGFR L858R mutated NSCLC, treated with erlotinib
Enlarge  Figure 1-2: 1/31/12: progressive disease now with acquired EGFR T790M mutation,
Figure 1-2: 1/31/12: progressive disease now with acquired EGFR T790M mutation,
Enlarge  Figure 1-3: treated with afatinib followed by afatinib+cetuximab
Figure 1-3: treated with afatinib followed by afatinib+cetuximab
Enlarge  Figure 1-4: 1/31/15: stable disease with acquired EGFR T790M mutation, continued on afatinib+cetuximab
Figure 1-4: 1/31/15: stable disease with acquired EGFR T790M mutation, continued on afatinib+cetuximab
Enlarge  Figure 1-5: 10/15/15: progressive disease with maintained EGFR T790M mutation, treated with Osimertinib
Figure 1-5: 10/15/15: progressive disease with maintained EGFR T790M mutation, treated with Osimertinib
Enlarge  Figure 1-6: 6/13/16: progressive disease with loss of EGFR T790M but maintained L858R mutation, treated with erlotinib
Figure 1-6: 6/13/16: progressive disease with loss of EGFR T790M but maintained L858R mutation, treated with erlotinib
Enlarge  Figure 1-7: 8/5/16: progressive disease, enrolled in hospice
Figure 1-7: 8/5/16: progressive disease, enrolled in hospice

Pathology - Part 1

Enlarge  Figure 1-8: 6/20/16: right lung fine needle aspirate cell block
Figure 1-8: 6/20/16: right lung fine needle aspirate cell block
Enlarge  Figure 1-9: 6/20/16: high power with malignant glands
Figure 1-9: 6/20/16: high power with malignant glands
Enlarge  Figure 1-10: 6/20/16: right lung core biopsy cell block, TTF-1 positive consistent with lung adenocarcinoma
Figure 1-10: 6/20/16: right lung core biopsy cell block, TTF-1 positive consistent with lung adenocarcinoma
Enlarge  Figure 1-11: 6/20/16: right lung core biopsy cell block, invasive malignant glands consistent with lung adenocarcinoma
Figure 1-11: 6/20/16: right lung core biopsy cell block, invasive malignant glands consistent with lung adenocarcinoma

Pathology - Part 2

  • Biomarker testing on 6/20/16 sample
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Enlarge  Figure 1-17: H&E section used for biomarker testing
Figure 1-17: H&E section used for biomarker testing

Pathology - Part 3

Enlarge  Figure 1-18: EGFR CISH - Area 1 x 40
Figure 1-18: EGFR CISH - Area 1 x 40
Enlarge  Figure 1-19: EGFR CISH - Area 2 x 40
Figure 1-19: EGFR CISH - Area 2 x 40
Enlarge  Figure 1-20: PTEN IHC – Area 1 x 20
Figure 1-20: PTEN IHC – Area 1 x 20
Enlarge  Figure 1-21: PTEN IHC – Area 2 x 20
Figure 1-21: PTEN IHC – Area 2 x 20

Proposed potential therapies

  • Summary
Enlarge 

Discussion

  • This patient’s case illustrates a decade of management for advanced EGFR-mutated adenocarcinoma of the lung.
  • Although she was treated with curative intent with concurrent chemoradiation (cisplatin-based chemotherapy for four cycles), she developed biopsy-proven metastatic recurrence twenty months later.
  • There was value in fresh tissue biopsies at times of progression to guide treatment recommendations.
  • Because of the sensitizing EGFR mutation at L858R, she received erlotinib which resulted in a two year progression free interval.
  • The L858R mutation occurs within exon 21 and is the second most common EGFR mutation in NSCLC, accounting for 40% of cases.
  • This mutation results in activation of the tyrosine kinase domain and is sensitive to small molecule tyrosine kinase inhibitors such as erlotinib.
  • Most patients develop resistance to first generation EGFR TKIs within 8 to 16 months of treatment.
  • The mechanism of resistance in more than 50% of cases is due to the acquisition of a T790M mutation.
  • Erlotinib binds in a reversible manner to the adenosine triphosphate (ATP) binding site of EGFR tyrosine kinase, inhibiting the initiation of signaling cascades.
  • Afatinib is an oral irreversible ERBB family blocker that covalently binds to the cysteine residue of EGFR.
  • At the time of this patient’s progressive disease, afatinib was not FDA approved.
  • She was treated on an early phase trial with afatinib and maintained a response for six months.
  • Although afatinib has been considered for treatment in patients who have progressed after first-line EGFR treatment, data from LUX-Lung 1 indicate that there is no improvement in median overall survival with afatinib when compared with placebo.*
    • * Miller VA et al. Lancet Oncol 2012;13:528-538.
  • At time of progression on the early phase trial, she was able to cross-over to the combination of afatinib plus cetuximab.
  • She maintained a response for over three years.
  • This combination regimen may be useful for patients who have progressed after receiving an EGFR TKI and chemotherapy.
  • Based on phase Ib data, patients with T790M mutations have a similar response rate in comparison to those without the resistant mutation (32% versus 25%, p=0.341).*
    • * Janjigian YY et al. Cancer Discov 2014;4:1036-1045.
  • Osimertinib is an oral TKI that inhibits both EGFR sensitizing mutations and T790M mutations that was FDA approved on 11/13/2015 for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, who have progressed on or after EGFR TKI therapy.
  • At time of progression and approval of this agent, this patient changed treatment from afatinib-cetuximab to osimertinib.
  • She continued on osimertinib for six months.
  • In the two studies that led to approval of osimertinib the overall response rate was 57% and 61%, and the median duration of response had not been reached. The dose finding phase of the studies showed a median DOR of 12.4 months.*
    • * http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208065s000lbl.pdf
  • At time of progression on osimertinib, she underwent repeat biopsy at a site of progression to assess for additional acquired resistant mutations.
  • C797S is one EGFR mutation that has been identified after progression on osimertinib.
  • Acquired resistance may also be associated with histologic transformation to small cell lung cancer.
  • This patient had neither, but she did have loss of T790M and maintenance of the EGFR L858R mutation.
  • Given that she had not received erlotinib for four and a half years and the T790M mutation was no longer identified, erlotinib was prescribed as her final therapy.
  • This was well tolerated but not effective.
  • Short interval imaging was consistent with progressive disease.
  • She was enrolled in hospice before succumbing to her disease one month later.

This patient never received cytotoxic chemotherapy in the metastatic setting. She received targeted therapy for nearly a decade which was well-tolerated with aggressive supportive management. Her treatment adjustments were always based on fresh tissue/plasma genomic assessments.

 

 

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