Tsao Picks Second-Line Therapy for a Patient With EGFR Exon 20+ NSCLC

Anne S. Tsao, MD

Professor, Section Chief, Program Chair

Department of Thoracic/Head and Neck Medical Oncology

Director, Department of Mesothelioma Program

Clinical Medical Director,Department of Thoracic and Orthopedic Center ad interim

The University of Texas MD Anderson Cancer Center

Houston, TX

CASE:

• A 64-year-old man presented with worsening fatigue, persistent dry cough, and mild progressive dyspnea over last month, with some chest discomfort, especially during routine exercise; unintentional weight loss of 8 lbs over last 4 months​
• Medical history: hypertension and hypercholesterolemia, both well controlled with medication​
• Family history: father of 2 teenage children, never smoker, no other notable medical history​
• Patient evaluation: right lower lobe auscultation reveals decreased breath sounds​
• ECOG performance score: 1​
• CT of chest: 3.5-cm mass in right lower lobe, small right pleural effusion with nodularity; mediastinal lymph nodes​
• PET/CT: multiple bone metastases, including vertebrae and left scapula​
• Brain MRI: negative for brain metastasis​
• Mediastinal node endobronchial ultrasound: non–­small cell lung cancer (NSCLC) TTF1+ adenocarcinoma; stage IVB​

TARGETED ONCOLOGY^TM: What factors determine your first-line treatment approach for this patient?

ANNE TSAO, MD: The KEYNOTE-189 [NCT02578680] regimen, which is a platinum-based agent/pemetrexed plus an immunotherapy, certainly is favored for patients with PD-L1 expression of less than 50%.¹ But this is a never-smoking patient with adenocarcinoma so there is a risk that they’re going to have an oncogenic driver mutation, and giving them an immunotherapy triplet regimen is probably not in their best interests. So, that is an important point for this case.

CASE (continued):

• Patient was started on chemotherapy doublet (cisplatin and pemetrexed)​
• Tissue next-generation sequencing showed EGFR exon 20 insertion mutation (V769_D770insASV)​
• Now 4 months after initiation of chemotherapy (with initial partial response) patient is reporting worsening back pain and shortness of breath​
• CT scan shows disease progression​
• Repeat brain MRI shows no metastases​

What are the characteristics of an EGFR exon 20 insertion?

This is rare, and [many physicians] have not experienced EGFR exon 20 insertion mutations yet. This type of a mutation can be characterized as an inframe insertion, or it can be a duplication.² So, you might see either of those words when you look at a patient’s molecular profile. Both of them, however, will have responses to targeted therapy drugs.

These are mostly considered mutations that are mutually exclusive from other mutations in NSCLC. We typically will see them in women, never-smokers, and Asian patients. We see these a lot in the adenocarcinoma histology; I’ve never seen one in squamous or large-cell disease. These are pretty rare, they’re about 6% of our overall population.

Now, when you look at the binding pocket of the receptor, for the sensitizing EGFR mutations, which are the deletion exon 19 and the L858, they have a different conformation in the binding pocket. The exon 20 insertion generally will not be responsive or sensitive—because of the way the binding pocket is structured—to first- and second-generation EGFR tyrosine kinase inhibitors [TKI]. Typically, you can’t use other agents like gefitinib [Iressa] and erlotinib [Tarceva], in patients with EGFR exon 20 mutations.

What therapy would you choose in the next line for a patient with an EGFR exon 20 insertion who received chemotherapy?

Chemotherapy plus an immunotherapy is probably not the route you want to take. For the patients with EGFR and ALK alterations, you want to reserve and not give them immunotherapies because of the risk of pneumonitis when you give them an EGFR-targeted therapy. We believe that this is going to be the case for any small-molecule TKI for these patients. So, amivantamab [Rybrevant] and mobocertinib [Exkivity] are certainly very viable options for this patient.

The FDA approval announcement for amivantamab came [in May 2021], but the mobocertinib was approved September 2021.^3,4 It is an indication for EGFR exon 20 insertion mutations that are detected by an improved test. The Oncomine Dx Target Test was the assay that received approval at that same time.³ The overall response rate [ORR] was 28% with a median duration of response [DOR] of 17.5 months. Which is why, for this rare tumor population, the mobocertinib received its approval.

Please discuss the study design and patient population of the CHRYSALIS trial (NCT02609776).

CHRYSALIS was a phase 1 study of only patients who had EGFR exon 20 insertion mutations. They had to progress on prior platinum therapy, and patients were looked at in a dose-escalation phase 1, and then a dose-expansion phase 2. The primary end points were dose-limiting toxicity and ORR. If you look at the phase 2 dosing, what was recommended was the 1050 mg dose of amivantamab, given once weekly for the first 4 weeks, and then every 2 weeks later on.⁵ The enrollment criteria were pretty typical, where patients had to be metastatic with an ECOG performance score of 0 or 1.

In the [dose escalation] population, about 60% of the patients were non-smokers, just like our patient in this case. Then, in the efficacy population, it was about 53% who never smoked. In terms of median lines of prior therapy for the dose-escalation phase, there were a median of 3 lines of prior therapy, so heavily pretreated with chemotherapy. And then, in the efficacy population, there were a median of 2 lines of prior therapy.

What were the results of the trial in terms of efficacy?

When we look at the efficacy results, the ORR was 40% for the patients. In there, it’s important to note there were 3 complete responses. There were some major responses, as well. Overall, there were 29 partial responses. The median DOR was 11.1 months, and then 75% of the responses were all seen with the first disease assessment. This was very promising, exciting data from CHRYSALIS.

This is not like the sensitive EGFR mutations, where you get remarkable responses with well over a year and a half median DOR with osimertinib [Tagrisso]. This is a different patient population. But this is the best we have so far for the EGFR exon 20 insertion mutation.

What was the safety and tolerability observed in the CHRYSALIS trial?

In terms of adverse events [AEs], not surprisingly, rash and paronychia are the main toxicities, just like what we see with the other EGFR-targeted therapies. But also, because it is an intravenous drug, infusion reactions do occur with this agent. And because you’re giving it weekly for the loading doses—I do 2 months of the loading dose weekly before going to every other week—it’s a concern we have to watch out for.

When we look at all AEs, the rate of grade 3 or higher AEs for the safety population was 35%; and then the treatment discontinuation rate was 10%. Dose reductions were needed in 13%, and dose interruption was done in 35%. Typically, we have to dose interrupt due to the rash.

_References:

_{1. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092. doi:10.1056/NEJMoa1801005}

_{2. Meador CB, Sequist LV, Piotrowska Z. Targeting EGFR exon 20 insertions in non-small cell lung cancer: recent advances and clinical updates. Cancer Discov. 2021;11(9):2145-2157. doi:10.1158/2159-8290.CD-21-0226}

_{3. FDA grants accelerated approval to amivantamab-vmjw for metastatic non-small cell lung cancer. FDA. Published May 21, 2021. Accessed May 10, 2022. https://bit.ly/3spnlPw}

_{4. FDA grants accelerated approval to mobocertinib for metastatic non-small cell lung cancer with EGFR exon 20 insertion mutations. FDA. Published September 15, 2021. Accessed May 10, 2022. https://bit.ly/3Pbg5AH}

_{5. Park K, Haura EB, Leighl NB, et al. Amivantamab in EGFR exon 20 insertion-mutated non-small-cell lung cancer progressing on platinum chemotherapy: initial results from the CHRYSALIS phase I study. J Clin Oncol. 2021;39(30):3391-3402. doi:10.1200/JCO.21.00662}