Clinical vignettes
A 55-year-old female was started on therapy with Erlotinib 150 mg daily 1 year ago for her Stage IV lung adenocarcinoma. Baseline imaging revealed bilateral lung, several bone and bilateral adrenal gland metastasis. Brain MRI was negative for any lesions. Next generation sequencing of her tumor revealed an Exon 19 mutation in EGFR. She initially had a robust partial response until a recent restaging scan confirmed progression of disease. A biopsy of an enlarging right adrenal gland metastasis reveals a T790M mutation in exon 20. Which of the following medications do you start?
Osimertinib
The EGFR T790M mutation is the most common mechanism of drug resistance to EGFR tyrosine kinase inhibitors.
Tagrisso (osimertinib) is approved for patients whose tumors have a T790M mutation in EGFR and whose disease has progressed after treatment with other EGFR-blocking therapy.
FDA approved for the first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations.
What are the most common EGFR mutations
Exon 19 (del), L858R (exon 21), T790M (exon 20)
What should be started before Pemetrexed
Agents used for ROS-1 fusions
Crizotinib and Entrectinib
A 60-year-old female has recently been diagnosed with Stage IV NSCLC with liver and bone metastasis. Pathology has not signed out the case yet, so it is unclear which subtype of cancer she has. She has read on the internet about mutation testing in lung cancer, specifically EGFR, BRAF ALK, MET, RET, PD-L1, Her2 and ROS1. Which of the following situations is one where you would not necessarily test for an EGFR mutation?
A. Squamous histology, heavy smoker
B. NSCLC NOS
C. Large cell cancer
D. Squamous histology, never smoker
E. Adenocarcinoma
A) Squamous histology, heavy smoker
Patients with NSCLC who harbor an actionable EGFR mutation have a superior response rate and PFS with EGFR tyrosine kinase inhibitors (ie, Osimertinib, Erlotinib).
In the United States, about 15% of patients with lung adenocarcinoma harbor EGFR mutations.
While patients with non-squamous histology are normally tested, a patient with squamous cell histology who is a never smoker should be tested.
A 54-year-old male with a history of Multiple sclerosis presents with Stage IV NSCLC. He has a 80 pack-year smoking history and still smokes 1 pack-per-day. A staging brain MRI is negative. PET-CT reveals 4 liver lesions and bilateral lung disease. A liver lesion is biopsied and the patient has squamous cell cancer consistent with a lung primary. The final pathology reveals pure squamous histology. PD-L1 expression is 25%. Which of the following treatments do you recommend for him?
A. Carboplatin + paclitaxel + bevacizumab
B. Carboplatin + pemetrexed
C. Carboplatin + paclitaxel
D. Carboplatin + paclitaxel + pembrolizumab
E. Pembrolizumab
D) Carboplatin + Paclitaxel
Bevacizumab and Pemetrexed are indicated for Non-squamous histology.
The FDA has approved pembrolizumab in combination with carboplatin and either paclitaxel or nab-paclitaxel as first-line treatment of metastatic NSCLC. Approval was based on KEYNOTE-407. Rregardless of PD-L1 tumor expression status, who had not previously received systemic therapy for metastatic disease.
In addition, with his PD-L1 ≥1% (but <50%), one could offer Pembrolizumab as monotherapy or Nivolumab/Ipilimumab as treatment.
However, with this patient's history of Multiple Sclerosis, offering immunotherapy would be too risky either as monotherapy or in combination with chemotherapy.
A tumor > X cm upstages to stage III
7 cm
What is the most common fusion partner for ALK?
EML4
Agents used for BRAFV600e mutation
Dabrafenib/Tametinib
A 52-year-old male comes to see you for a second opinion for his recently diagnosed Stage IV NSCLC. He has a 10-pack-year smoking history, but quit over 20 years ago. PET-CT at the outside facility showed bilateral lung lesions along with a left adrenal lesion; the latter was biopsied showing adenocarcinoma. Brain MRI is negative. He has some dyspnea, hemoptysis and overall fatigue. He has no other comorbid conditions. He is quite symptomatic, so treatment will need to be started soon. Which of the following is the least reasonable thing to do at this time?
A. Start therapy with Carboplatin + Paclitaxel + Bevacizumab
B. Start therapy with Carboplatin + Pemetrexed + Pembrolizumab
C. Send for PD-L1, ALK, BRAF, ROS1, EGFR and other targetable mutations
D. Start therapy with Carboplatin + Pemetrexed
E. None
A) Start therapy with Carboplatin + Paclitaxel + Bevacizumab
Ideally if he has minimal symptoms, would send for PD-L1, ROS1, BRAF, EGFR, and ALK mutation testing. He has a decent chance of having one given his histology (adenocarcinoma) and not having an extensive smoking history. In fact, many would just send for Next Generation sequencing.
This patient is having hemoptysis. As such, bevacizumab would be contraindicated.
Of note, if this patient were started on therapy with a regimen such as Carboplatin/Pembrolizumab +/- Pemetrexed and is found to have an actionable mutation (ie, EGFR mutation), then one can switch his therapy. Immunotherapy does not work as effectively in patients with advanced NSCLC who harbor an actionable mutation.
A 47-year-old male is on Crizotinib as frontline therapy for his Stage IV Lung adenocarcinoma. Baseline genomic profiling revealed a ALK-EML4 rearrangement. At the time the patient started therapy, Crizotinib was the only ALK inhibitor available. He has been on therapy for 12 months and he has had a complete response of his known 3 lung and 2 liver lesions. The baseline Brain MRI was negative for metastasis. You receive a call from his wife that he has been having worsening headaches. A Brain MRI is ordered and reveals a solitary 1 cm right frontal lobe lesion. A PET-CT reveals no other evidence of disease. What do you recommend at this time?
A. SRS to the brain lesion, continue Crizotinib
B. Switch therapy to Alectinib
C. Switch therapy to Ceritinib
D. Switch therapy to Carboplatin + Pemetrexed
E. SRS to the brain lesion, switch to Alectinib
A) SRS to the brain lesion, continue Crizotinib
Outside of the solitary brain lesion that has developed, this patient’s lung cancer has under outstanding control with Crizotinib. In this case, would perform stereotactic radiation to the solitary brain lesion and keep the effective systemic therapy going.
The newer ALK inhibitors, such as Alectinib, Brigatinib and Lorlatinib, have increased brain penetration and can shrink brain metastases.
Which agents should only be used in non-squamous histology?
Pemetrexed and bevacizumab
AE of bevacizumab
GI perforations, wound healing complications, bleeding complications, thromboembolic events, hypertension, proteinuria, infusion reactions
Agents used for RET fusions
Selpercatinib
A 72-year-old male with a 40-pack-year smoking history presents to see is PCP for a 2 week history of hemoptysis. A full workup is performed that shows a 6 cm right lower lung mass that is abutting the diaphragm. PET-CT imaging reveals no other sites of disease and a Brain MRI is negative. A biopsy is performed of the RLL lung mass and he is found to have a lung adenocarcinoma. Bronchoscopy with EBUS is performed and all sampled mediastinal lymph nodes are negative for cancer. PFTs are near normal. The patient is discussed at tumor board and he is deemed to have resectable disease. What should be offered to this patient?
A. Concurrent chemoradiation
B. Concurrent chemoradiation followed sequentially by Durvalumab
C. Sequential chemotherapy followed by Radiation
D. Surgery followed by adjuvant chemotherapy
E. Surgery followed by adjuvant Durvalumab
D) Surgery followed by adjuvant chemotherapy
For patients with NSCLC that is T4, N0-1 (Stage IIIA), one should offer surgery if the patient has resectable disease. If the patient undergoes surgery and achieves negative margins (R0), then adjuvant chemotherapy should be offered.
Alternatively, if a patient has T4, N0-1 (Stage IIIA) disease that is unresectable, then definitive concurrent chemoradiation followed sequentially by Durvalumab should be offered.
A T4 tumor is defined as one >7 cm in size or a tumor invading one or more of the following:
Diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina
A 36-year-old male was diagnosed with ALK-EML4 rearranged, Stage IV NSCLC. Baseline imaging reveals that he has both liver and lung lesions. He was started on Crizotinib initially as this was the only ALK inhibitor approved at the time. He enjoyed a partial response to Crizotinib that lasted for almost 2 years. Unfortunately, restaging scans show progression of disease in his liver. A brain MRI remains negative for CNS metastasis. What therapy do you offer?
Alectinib
There are currently 3 ALK inhibitors approved in the 2nd line setting in patients who have progressed on frontline Crizotinib. These include ceritinib, alectinib and brigatinib. Lorlatinib is approved for patients whose disease has progressed on crizotinib and at least one other ALK inhibitor for metastatic disease or whose disease has progressed on alectinib or ceritinib as the first ALK inhibitor therapy for metastatic disease.
It was demonstrated to have significant central nervous system activity (over 60% in some studies).
IHC staining for adenocarcinoma and squamous
Adenocarcinoma- TTF+, cytokeratin 7+/20-
Squamous- p63, p40
What are the FDA approvals of Pembrolizumab in 1st line?
Agents used for MET exon 14 splice mutation
Capmatinib
A 54-year-old male with an 80-pack-year smoking history presents with dyspnea and coughing for the past 8 weeks. CXR reveals a 5 cm RUL lung mass. CT Chest with IV contrast shows no pathologic appearing LAD. He is found to have a right-sided pleural effusion. He undergoes a diagnostic and therapeutic thoracentesis. Pathologic analysis of the pleural fluid reveals squamous cell lung cancer. PD-L1 expression is 0%. PET-CT reveals no other evidence of disease and his Brain MRI is negative. What treatment would you recommend?
A. Surgery and adjuvant chemotherapy
B. Mediastinoscopy with EBUS
C. Radiation (SBRT) given the solitary mass
D. Palliative Carboplatin + Taxol +/- Pembrolizumab
E. Erlotinib 150 mg daily
D) Palliative Carboplatin + Taxol +/- Pembrolizumab
Malignant pleural effusions connote Stage IV disease. This patient is not a surgical candidate and one should offer palliative chemotherapy (or clinical trial) if his performance status allows for it.
For this patient, either doublet chemotherapy or doublet chemotherapy (Carboplatin/Taxol) with immunotherapy would be reasonable option. With a PD-L1 level of 0%, another option would be Nivolumab, Ipilimumab + Paclitaxel + Carboplatin.
A 46-year-old male has just been diagnosed with stage IV Lung adenocarcinoma. Baseline imaging reveals 3 liver lesions and bilateral lung lesions. A liver lesion is biopsied and confirms the diagnosis. The patient is a never smoker. He undergoes next generation sequencing. The report comes back showing that he has a G719X mutation in EGFR (not an EGFR 19 or 21 deletion). PD-L1 is 25%. What therapy do you offer?
A. Erlotinib
B. Keytruda
C. Carboplatin + Alimta
D. Afatinib
E. Alectinib
D) Afatinib
The FDA has approved Gilotrif (afatinib) to treat first-line, non-small cell lung cancer patients bearing the L861Q, G719X and S768I EGFR mutations.
The FDA had initially approved the drug to treat first-line patients with EGFR exon 19 deletions or exon 21 L858R mutations.
What are the AE of lorlatinib?
Hypercholesterolemia, hypertriglyceremia, edema, weight gain
What are the FDA approvals for atezolizumab in 1st line?
All but which ALK inhibitor has CNS penetration and control.
Crizotinib
A 64-year-old male comes to see you for a second opinion for metastatic lung adenocarcinoma. He has disease in the bilateral lung fields and 5 subcentimeter brain metastasis. Kidney and Liver function tests are WNL. Baseline analysis reveals no actionable mutations and PD-L1 expression is 5%. He has completed WBRT and comes to see you for systemic options. Given his history of Guillain-Barre syndrome, immune therapy is not felt to be an option. His ECOG PS=1. Which of the following is false?
A. After 4-6 cycles of doublet chemotherapy, there is data for PFS and OS benefit with maintenance pemetrexed
B. If Cisplatin/Pemetrexed is started, he should be on folic acid daily (450 mcg) and B12 shots q 9 weeks to help ameliorate myelosuppressive side effects
C. Carboplatin/Paclitaxel/Bevacizumab (ECOG 4599) is absolutely contraindicated due to his brain metastasis
D. Given his PS, doublet-therapy is more appropriate than single agent
E. None
C) Carboplatin/Paclitaxel/Bevacizumab (ECOG 4599) is absolutely contraindicated due to his brain metastasis
This regimen is not commonly deployed anymore as immunotherapy is normally offered as part of frontline therapy for patients with advanced lung cancer. However, for patients with metastatic disease, this remains an acceptable treatment option.
He has _treated_ brain metastasis, so bevacizumab can be given (albeit with caution)
**Pearl:
Bevacizumab side effects to be aware of include:
Nephrotic syndrome, strokes, DVT, poor wound healing, perforated viscus