Discussing Response of Amivantamab in EGFR Exon 20+ NSCLC

CASE

• A 64-year-old Asian woman presented with persistent dry cough and mild progressive dyspnea over the last month. During this time, she had an unintentional weight loss of 8 lbs.
• Medical history: Hypertension and hypercholesterolemia​
• Smoking history: Never smoker​
• Physical exam: Right lower lobe auscultation reveals decreased breath sounds​
• ECOG performance status: 1​
• CT chest scan: 3.5 cm mass in right lower lobe, small right pleural effusion with nodularity; mediastinal lymphadenopathy
• PET/CT scan: multiple bone metastases, including vertebrae and left scapula​.
• Brain MRI was negative for brain metastases.
• Mediastinal node endobronchial ultrasound: Non–small cell lung cancer (NSCLC) TTF1 positive adenocarcinoma; stage IVB​
• Negative PD-L1 expression
• Results of next-generation sequencing (NGS) pending
• The patient was started on chemotherapy doublet (cisplatin and pemetrexed)​.
• Tissue NGS showed EGFR exon 20 insertion mutation (V769_D770insASV)​.
• Four months after initiation of chemotherapy with initial partial response, the patient reported worsening back pain and shortness of breath​.
• CT scan showed disease progression​.
• Repeat brain MRI showed no metastases.

Targeted Oncology: What was the design of the CHRYSALIS study (NCT02609776)?

MARTIN F. DIETRICH, MD, PHD​: The CHRYSALIS study is a prospective evaluation of amivantamab-vmjw [Rybrevant] in the NSCLC setting and is a two-part study looking at dose escalation, with an eventual dose finding of 1400 mg for patients [weighing] over 80 kg and 1050 mg for patients [weighing less than] 80 kg with dose expansions.¹ It was also a multicohort study [focusing on] patients in cohort D with EGFR exon 20 insertion [positive NSCLC], but based on the mechanism of action they're also looking at [more cohorts].

Martin F. Dietrich, MD, PhD​Assistant Professor of Internal Medicine

University of Central Florida in Orlando​

Orlando, FL​

[This included] patients with post–EGFR inhibitor disease progression with a C797S mutation, patients with MET amplifications post EGFR, which is more common than [seeing patients with the] C797s mutations...and then…patients that are positive with a MET exon 14 skipping mutations, which certainly plays a role in this disease. Patients on the study were allowed to [enroll if they] have brain metastases and were previously treated, but they needed to have the confirmation of an EGFR exon 20 mutation.¹ So, it's a versatile study that certainly has the impact of changing our practice in several directions.

What was the baseline characteristics of patients on this study?

Looking at the trial enrollment, it was an international study with [an even] distribution between an Asian and White patient population.¹ There [was also] a diverse background of smoking and was a largely metastatic disease space. In terms of pretreatment, about 40% had immunotherapy prior to treatment and about 77% in the treatment population had an EGFR tyrosine kinase inhibitor [TKI] upfront.¹

What was the efficacy of this study?

The overall response rate was 40% [95% CI, 29%-51%], about 4% were complete responses, and 36% were partial responses. We did see a fair amount of additional disease stabilization with a disease control rate of about 90%.¹ So, this is an agent...[where] the vast majority of patients will have disease stabilization, or even [tumor] shrinkage, but not necessarily meeting the full cutoff for EGFR mutations. The median duration of response was [11.1 months (95% CI, 6.9–not reached)], the median progression-free survival was 8.3 months [95% CI, 6.5-10.9], and the median overall survival was not ready for finalization. It was roughly about 2 years at the current level [of 22.8 months].¹

What notable adverse events were there with amivantamab, and how does it impact the use of this drug?

In my experience, rash is probably the most common concern [for patients on amivantamab, which was the case in the study as 4% had grade 3/4 rash].1 However, this is not surprising when you have an EGFR mutation that is not mutation specific. The extracellular domain is not different between oncogenic and wild-type EGFR, so it's not surprising that [rash] occurs. We know that from other EGFR inhibitor applications by antibody blockade, that they're [still] prognostically favorable. This is certainly one that I feel is more manageable, as we manage similar [toxicities] like this with antibiotics...and maybe even steroids if necessary.

A very interesting feature [of this therapy] are infusion-related reactions. I like to think of this as a similar pattern of reaction like we do with rituximab [Rituxan], where the first infusion is the roughest of a target saturation and then immune activation occurs. As the infusions go on…when the infusion is broken up into 2 days, it typically gets easier, and then we're moving from longer and more challenging infusions down to a shorter and less troublesome infusion. So, I think this is a mechanism of immune attenuation that is not consistent with an allergic type of reaction, but more of an immune engagement type [of reaction].

^Reference

^{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}