Identifying Second-Line Options for NSCLC With EGFR Exon 20 Insertions

Christine Bestvina, MD

Assistant Professor of Medicine

Comprehensive Cancer Research Center

University of Chicago Medicine

Chicago, IL

CASE SUMMARY

A 64-year-old man presented with worsening fatigue, persistent dry cough, and mild progressive dyspnea over the last month, with some chest discomfort, especially during routine exercise, and unintentional weight loss of 8 lbs over the last 4 months​. He had a history of well-controlled hypertension and hypercholesterolemia​. The patient is a father of 2 teenage children, never smoked, and has no other notable medical history​.

Right lower lobe auscultation revealed decreased breath sounds​, and he received an ECOG performance score of 1. A CT scan of the chest showed a 3.5-cm mass in the right lower lobe, a small right pleural effusion with nodularity and mediastinal lymph nodes. PET/CT showed multiple bone metastases including the vertebrae and left scapula. Brain MRI was negative for metastases. A mediastinal node endobronchial ultrasound confirmed a diagnosis of non–small cell lung cancer (NSCLC) stage IVB thyroid transcription factor 1-positiveadenocarcinoma.

Molecular testing showed negative PD-L1 expression, and while pending results of tissue DNA next-generation sequencing (NGS), the patient was started on chemotherapy doublet (cisplatin and pemetrexed)​. Tissue NGS showed an EGFR exon 20 insertion mutation (V769_D770^InsASV)​. Now, 4 months after initiation of chemotherapy with initial partial response, the patient is reporting worsening back pain and shortness of breath​, and a CT scan shows disease progression.

DISCUSSION QUESTION

• Please discuss your preferred second-line treatment for this patient.

KARIM ANWAR, MD: Amivantamab [Rybrevant] and mobocertinib [Exkivity] are approved for this indication.^1,2 But…I think in [National Comprehensive Cancer Network (NCCN) guidelines], any one of them could be chosen, but I do not know how they compare with each other.³

RON SHADE, MD: I would agree. In NCCN [guidelines], both agents are approved for this exon insertion 20, so I think those would probably be the best 2 choices. I haven’t used either agent, and I’m not that familiar with the differences between the 2, why some patients would be better served with one versus the other. I’m not really sure which I would use of those 2.

MURUGAVEL MUTHUSAMY, MD: [I know that amivantamab] is an antibody given IV [intravenously], but I have never used [amivantamab or mobocertinib].

MELHEM JABBOUR, MD: I would try amivantamab, and if he progresses, we’ll go with [mobocertinib]. I don’t have experience [with them]. I know in NCCN guidelines, they’re both there. Maybe if he progresses on one, we’ll go with the other.

SHADE: I thought of it like erlotinib [Tarceva] versus afatinib [Gilotrif], just 2 TKIs [tyrosine kinase inhibitors] that are both appropriate, but maybe have different adverse event profiles, so that might be what we would base it on.

NISHANT PODDAR, MD: I’ve not used it. I use the Guardant platform a lot, and I think [Guardant360 CDx liquid biopsy] was approved [as a companion diagnostic] with amivantamab.¹ Amivatamab got approved in May 2021 based on its 40% overall response rate [in the phase 1 CHRYSALIS trial (NCT02609776)].⁴

I don’t know much about mobocertinib. I think it got approved later on, so that’s why I picked [amivantamab].

CHRISTINE BESTVINA, MD: Exactly as all of you know already, at time of progression for patients who have EGFR exon 20 insertions, the 2 NCCN recommended subsequent therapies are amivantamab and mobocertinib.³ What is important to know is that these patients with EGFR exon 20 insertions do not, and should not as of today, receive this therapy in the frontline. So, these patients should get other systemic therapy first, before going on to receive 1 of these 2 agents.

The question of sequencing was brought up, and what we do not know currently is what the appropriate sequencing should be of these 2 agents, but we do know that you can go between agents. And so, NCCN guidelines say whatever you pick as your [next] line, at time of progression, you should switch agents.

SHADE: In terms of the first-line [therapy], I thought that these particular mutations don’t respond that well to other targeted therapies, so are you saying that we should use a platinum doublet as first-line? Let’s say we get our NGS information promptly. [Both approved agents] are second-line, so we should still start with a platinum doublet, and then on progression, then switch to [one of these]?

BESTVINA: That’s exactly right. So this patient, appropriately, received chemotherapy up front. Where the huge debate in the field is right now is about the addition of immunotherapy for this group, and should they receive just carboplatin/pemetrexed; should they receive carboplatin/pemetrexed plus pembrolizumab [Keytruda]; and what that looks like, I think that’s a much more ambiguous realm. But, all the data we have for both of these agents right now are in the second-line setting, and they should receive chemotherapy up front.

ALKARIM TAJUDDIN, MD: Is the rationale for using chemotherapy first because of the poor responsiveness to this targeted therapy, or is it because chemotherapy brings a change to make it more responsive?

BESTVINA: It’s more the latter. First it’s a product of the clinical trial design. All of the data we have for amivantamab and mobocertinib right now is in the second-line or higher. The clinical trials that are pushing it to frontline therapy are happening now. Those trials are all randomized against frontline chemotherapy. And so, until we see those data, all of the current data that we have right now are for second-line or higher.

MUTHUSAMY: So, [amivantamab] is an antibody that only works on the surface. [Mobocertinib] is a TKI that works inside the cell. Do they have a [combination trial] for these drugs? That would be interesting.

BESTVINA: It has been brought up at certain meetings whether that could potentially be a viable strategy, but it is not, as of right now, in clinical trial design.

ISOKEN KOKO, MD: Until now, I don’t test patients with squamous cell carcinoma for mutations, except for PD-L1. Do I now have to consider routinely sending patients with these tumors for NGS?

BESTVINA: I’ve changed my practice, [since there are also targeted treatments for] MET exon 14 skip mutations. MET exon 14 skipping occurs in about 4% to 5% of patients with squamous cell carcinoma; to me, those data are enough for me to test all patients with squamous cell carcinoma. And so, I have been sending it for everybody.

MUTHUSAMY: The NILE study [NCT03615443] from 2 years ago showed a concordance between tissue and liquid biopsies [in several genetic markers for NSCLC].⁵ Did the NILE study also look into [liquid biopsy versus tissue biopsy] for a MET exon 14?

BESTVINA: It did not. So, neither of the big studies that looked at concordance between tissue and blood [biopsies] included MET exon 14, because at that point it wasn’t considered a targetable mutation. Both of those papers were from 2019.

_References

_{1. FDA grants accelerated approval to amivantamab-vmjw for metastatic non-small cell lung cancer. FDA. Published May 21, 2021. Accessed July 6, 2022. https://bit.ly/3P3yUoy}

_{2. FDA grants accelerated approval to mobocertinib for metastatic non-small cell lung cancer with EGFR exon 20 insertion mutations. FDA. Published September 16, 2021. Accessed July 6, 2022. https://bit.ly/3yLZvBn}

_{3. NCCN. Clinical Practice Guidelines in Oncology. Non–Small Cell Lung Cancer, version 3.2022. Accessed July 6, 2022. https://bit.ly/3uv48wX}

_{4. 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}

_{5. Leighl N, Page RD, Raymond VM, et al. Clinical utility of comprehensive cell-free DNA (cfDNA) analysis to identify genomic biomarkers in newly diagnosed metastatic non-small cell lung cancer (mNSCLC). Presented at: 2019 American Association for Cancer Research Annual Meeting; March 29-April 3, 2019; Atlanta, GA. Abstract 4460. Accessed July 8, 2022. https://bit.ly/3uywrLa}