Non-Small Cell Lung Cancer II

Introduction

• Virtual Molecular Tumor Board
• Patient: Non–small cell lung cancer
• Carolinas HealthCare System/Levine Cancer Institute
• Presented by: Dr. Gregory M. Brouse

Initial Diagnosis

A 76-year-old female former smoker presented with cough, leading her to undergo a chest X-ray, which showed a right upper lobe mass. The patient smoked 2.5 packs per day for 15 years and quit smoking more than 40 years earlier.

• August 2016: CT imaging of chest identified a large mass in the right suprahilar and peritracheal regions.
• August 2016: Endobronchial ultrasound biopsy on level IV lymph node was performed.
  • Non–small cell lung cancer (poorly differentiated adenocarcinoma; TTF-1 and CK7 immunostains were positive)
  • Molecular analysis was performed in house.
    • EGFR L858R mutated (detected with Roche cobas EGFR Mutation Test v2 – tumor tissue)
    • ALK wild-type
• August 2016: PET scan showed extrathoracic disease (right hilar and bilateral mediastinal lymph nodes, left adrenal gland, right hip bone metastases).
• August 2016 – September 2016: Palliative radiation therapy to right hip/sacrum (30 Gy in 10 fractions)
• August 2016: Initiated treatment on randomized clinical trial (erlotinib [Tarceva; Genentech, Astellas] +/- VEGF inhibitor)
  • Typical EGFR rash on face (treated with topical hydrocortisone then prednisone 10 mg), loose stools

Clinical Progress and Treatment

• September 2016: Brain MRI showed no evidence of central nervous system disease.
• October 2016: CT of chest/abdomen/pelvis (C/A/P) showed stable disease in lung.
  • Good performance status
• November 2016: Rash worsened to involve upper chest, back and extremities (doxycycline 100 mg).
• December 2016: Mid-cycle 6 of erlotinib +/- VEGF inhibitor – CT of C/A/P demonstrated radiographic progression in the lung and mediastinum.
  • Removed from study protocol
  • Recommendation for repeat bronchoscopy with tumor biopsy to assess T790M status (3 to 5 cores requested)
• December 2016: Because of increased pain in the jaw, patient underwent a CT of the soft tissue of the neck.
  • Osseous destructive mass involving the anterior left mandibular body
    • 2.4 cm x 8.0 cm in greatest orthogonal axial dimensions and 1.4 cm in craniocaudal dimensions
  • Level I lymphadenopathy
• December 2016 – January 2017: Palliative radiation therapy to left hemimandible (30 Gy in 10 fractions)
• December 2016: Endobronchial ultrasound with needle biopsy (22-gauge; four samples were obtained)
  • Continued presence of EGFR L858R mutation, but no T790M
• December 2016: Signed informed consent to allow recent biopsy sample to be sent for large panel genomic testing
  • Forthcoming treatment considerations: systemic chemotherapy (carboplatin/pemetrexed) vs. immunotherapy vs. ASCO clinical trial TAPUR
• January 2017: Developed mucositis from radiation therapy
• January 2017: Case was discussed at institution’s molecular tumor board.
  • BRAF/KRAS/NRAS wild-type – matched to cetuximab (Erbitux, Eli Lilly) on TAPUR
  • ATM - matched to olaparib (Lynparza, AstraZeneca) on TAPUR but requires ASCO TAPUR molecular tumor board reviewed
  • PD-L1 tumor proportion score (TPS) – 100%
• January 2017: Treatment recommendation was to start pembrolizumab (Keytruda, Merck), an anti–PD-L1 therapy, based on patient's high PD-L1 TPS.
• February 2017 – April 2017: Tolerating pembrolizumab well with minimal adverse effects
• April 2017: Restaging CT of chest, soft tissue neck demonstrating partial response
  • Brain MRI revealed a new enhancing intraparenchymal mass in the right frontal lobe of brain (14 mm x 7 mm x 11 mm).
  • Referral to radiation oncology for stereotactic radiosurgery (SRS)
• May 2017 – June 2017: SRS to right frontal lobe lesion; pembrolizumab was continued.
• June 2017: Restaging CT scans demonstrating disease progression
  • Right hilar mass increased.
  • Brain MRI identified second lesion that was too small to pick up on prior scan.
  • Decrease in size of other brain lesion
• July 2017: Palliative radiation therapy to right hilar mass
• July 2017: Liquid biopsy was performed.
  • If T790M present, options include osimertinib (Tagrisso, AstraZeneca).
  • T790M was not detected using Roche cobas EGFR Mutation Test v2. L858R mutation was identified.
• August 2017: Restaging scans showed no new sites of disease.
  • CT of abdomen demonstrated increasing adrenal gland mass and increasing size in left sacral mass.
  • Brain MRI was stable.
• August 2017: Initiated third-line treatment with carboplatin/pemetrexed
• September 2017: Palliative radiation to left sacrum
• September 2017: Cycle 2 was held to recover from small bowel obstruction and radiation.
• October 2017: Restaging CT of chest was stable.
• October 2017 – November 2017: Continued carboplatin/pemetrexed
• November 2017: Restaging scans
  • Brain MRI showed slight enlargement of left precentral gyrus lesion (3 mm → 5 mm).
  • CT of abdomen showed increasing size of left adrenal gland. CT of chest showed stable disease.

Imaging

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Pathology- Part 1

• Pathology Images – Initial Diagnosis: Right upper lobe, bronchoscopic biopsy, August 2016

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• Pathology Images – Initial Diagnosis: Right upper lobe

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Pathology- Part 2

• Pathology Images – Initial Diagnosis: Right upper lobe – TTF-1

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Pathology- Part 3

• Pathology Images – Initial Diagnosis: Lymph node

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• Pathology Images – Initial Diagnosis: Lymph node – TTF-1

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Pathology- Part 4

• Pathology Images – Repeat Biopsy: Lymph node, December 2016

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Genomic Panel Testing

Potential Treatments

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Targeted Therapies

• Afatinib (Gilotrif, Boehringer Ingelheim)
• Erlotinib (Tarceva; Genentech, Astellas)
• Gefitinib (Iressa, AstraZeneca)

Immunotherapies

• Atezolizumab (Tecentriq, Genentech)
• Nivolumab (Opdivo, Bristol-Myers Squibb)
• Pembrolizumab (Keytruda, Merck)

Tumor Mutational Load

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PD-L1 Tumor Proportion Score

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Discussion

• This case describes the course of treatment for an elderly patient with good initial performance status, an EGFR L858R mutation and high PD-L1 expression score.
• The patient was diagnosed with metastatic disease, and first-line treatment selection (clinical trial) was based on tumor marker status (EGFR L858R). Tissue was obtained by endobronchial biopsy, and testing was performed by the pathology group.
• While on trial protocol, the patient developed skin rash, indicating response to therapy¹ and remained on therapy for approximately 6 months before progressing in the left mandibular body. Rash improved over time with doxycycline (up to 100 mg daily). Despite an EGFR L858R mutation, the response to erlotinib was relatively short.
• Decision was made to re-biopsy the patient in the hopes of finding a new targetable mutation, such as EGFR T790M. More than 50% of patients with EGFR mutation who become resistant to therapy will harbor a T790M mutation.^2,3 
• Unfortunately, this patient did not have an EGFR T790M mutation, but results of next-generation sequencing indicated a 100% PD-L1 tumor proportion score (TPS).
• At the time of treatment, pembrolizumab⁴ was approved as an immunotherapy option for patients whose tumor had high PD-L1 TPS and had previous treatment with EGFR/ALK aberrations. Positive PD-L1 TPS was defined as ≥ 50%. If this patient’s PD-L1 score was < 50%, then platinum-based chemotherapy would have been recommended.
• The patient received 200 mg of IV pembrolizumab over 30-minute infusions on day 1 of a 21-day cycle. While on pembrolizumab, this patient experienced minimal toxicity. However, toxicity commonly associated with immune checkpoint inhibitors include dermatitis, hypophysitis, enterocolitis, elevated liver function and diarrhea. Additionally, patients who experience immune-related adverse events tend to have improved treatment outcomes.⁵
• After four cycles, the patient was reassessed. Stable disease was reported in her chest, and new central nervous system disease was identified. She was treated with SRS and continued pembrolizumab treatment for two additional cycles before having disease progression in the chest, despite the new brain metastasis. SRS was selected over whole brain radiation because of single site of disease and fewer comorbidities.  Pembrolizumab was continued as the patient only had new oligometastatic progression. Dose and schedule of pembrolizumab were not altered.
• Scans were obtained after cycle 6 was completed and identified progressive disease in the right hemithorax. At this point, the patient was re-biopsied for T790M mutation using a serum-based assay.  Liquid biopsies are good options for assaying several gene aberrations in patients with non–small cell lung cancer and are FDA approved in this indication. One advantage of using a liquid biopsy is that it allows for assessment of ctDNA in the bloodstream and may be more representative of the entire tumor burden.
• With no T790M mutation identified with liquid biopsy, the patient went on to salvage chemotherapy with carboplatin/pemetrexed. Of note, the patient continued to have an EGFR L858R mutation. Some studies have suggested re-treatment with an EGFR TKI after progression on EGFR TKI and chemotherapy, particularly in patients with no other treatment options.^6-8
• As of December 2017, the patient had received three cycles of carboplatin/pemetrexed without progression. However, a dose reduction for carboplatin is planned because of low hemoglobin.