Non-Chemotherapy Regimen Induces Encouraging Responses in Advanced EGFR-Mutant NSCLC

October 21, 2020
Danielle Ternyila
Danielle Ternyila

In an interview with Targeted Oncology, Alexander Spira, MD, PhD, discussed the findings from the clinical trial evaluating amivantamab in combination with lazertinib as treatment of patients with advanced EGFR-mutant non-small cell lung cancer.

Amivantamab (JNJ-61186372; JNJ-6372), an EGFR-MET bispecific antibody, in combination with the third-generation tyrosine kinase inhibitor (TKI) lazertinib induced high response rates as treatment of patients with advanced EGFR-mutant non–small cell lung cancer (NSCLC) in the phase 1 CHRYSALIS study (NCT02609776), which was presented during the European Society of Medical Oncology (ESMO) Virtual Congress 2020.

Among treatment-naïve patients, the objective response rate (ORR) was 100% (95% CI, 83%-100%), which included 20 partial responses (PRs), at a median follow-up of 7 months. At a median follow-up of 4 months, the ORR was 36% (95% CI, 22%-51%) in the osimertinib (Tagrisso)-resistant chemotherapy-naïve population, which included 1 complete response and 14 PRs.

In the treatment-naïve cohort, the median duration of treatment was 7 months (range, -10), and the time to first response was 1.5 months (range, 1.2-2.6). Among patients in the relapsed/refractory arm, the median treatment duration was 5 months (range, 0.3-15). Responses were observed regardless of whether they were treated in the first- or second-line of therapy, or had prior exposure to lazertinib.

These findings are particularly encouraging because this may offer patients a non-chemotherapy treatment alternative, and chemotherapy is the typical treatment for this patient population.

In an interview with Targeted Oncology, Alexander Spira, MD, PhD, director, Virginia Cancer Specialists Research Institute, and the Phase 1 Trial Program, discussed the findings from the clinical trial evaluating amivantamab in combination with lazertinib as treatment of patients with advanced EGFR-mutant NSCLC.

TARGETED ONCOLOGY: Could you provide some background to this combination regimen?

Spira: The CHRYSALIS trial is a great study because it's looking at a drug, amivantamab, with a completely different mechanism of action. It's a monoclonal antibody against EGFR. The idea with the study is combining a monoclonal with a small molecule TKI, called lazertinib, and there were 2 patient populations. One is the relapsed/refractory, so patients that received osimertinib before, and then there was a treatment-naive population as well. These are 2 different patient populations we looked at with this combination therapy.

TARGETED ONCOLOGY: What is the rationale for evaluating this combination?

Spira: If you look at the relapsed/refractory population, many patients, when they relapse, will have 1 of 2 mutations, either a C797S, or a c-Met mutation or amplification. That is the main area of resistance for most patients previously treated with an EGFR inhibitor, most commonly now osimertinib. This is a bispecific antibody, so it targets 2 things. It targets c-Met to hopefully overcome the c-Met resistance, and it targets EGFR in a different pathway. As a monoclonal, it binds the outside of the cell versus a small molecule that targets inside the cell. In essence, it's adding to the standard EGFR treatments. Lazertinib is very similar to osimertinib but adding a second drug to help overcome those mechanisms of resistance, so it's a very strong scientific rationale for the study.

TARGETED ONCOLOGY: What was the design of this trial and some of the key methods that were used?

Spira: The design of the study was very straightforward. It was a phase 1 that led to a phase 1B. It started off as a phase 1, dose finding study, and while there was concern of significantly increased toxicity, we didn't see a dramatic change when we used both a small molecule TKI and a monoclonal. Both drugs were able to be given at their regular doses, so there's no dose modifications needed. It was a very straightforward design for both these patient populations.

TARGETED ONCOLOGY: What are some of the key results that were presented at ESMO this year?

Spira: It was exciting because in the relapsed/refractory population, we saw about a 36% or 37% response rate, with significantly more patients benefiting as well. This is great because it's designed as a non-chemotherapy option and remembering that chemotherapy would be the normal approach for these patients. We now have a non-chemotherapy option, or at least studying a non-chemotherapy option, for these patients, so it's exciting in that the proof of concept did work.

The thought process behind the combining both drugs is that the monoclonal has less central nervous system penetration. Its monoclonal antibody, and those do not tend to penetrate the brain, so by continuing to administer with a small molecule, the idea is that you both be able to overcome resistance, as well as prevent brain recurrence, in addition to having a 2-fold attack on TKI therapy. It worked both in proof of concept and is also very exciting in terms of the results.

The second patient population with de novo patients actually had a 100% response rate, which is almost unheard of. Obviously, for the first-line therapy, we do have active therapies, but it's also exciting in both aspects. We did find standard EGFR toxicities or increased than we would typically [see]. Most commonly, these included nail changes or a little bit of a rash. Because of amivantamab is a fusional drug and a monoclonal, there were some infusion-related reactions, but with good monitoring, most patients were able to get it what we call split-dosing, so splitting the first dose over 2 days.

This is super exciting and showed very promising results. I think the key thing that will be coming down the pike, as we look at the results, is figuring out which patients benefited, and which do not. Is there a molecular mechanism behind it? Is it the molecular profile? Do the patients have any nutation or didn't have any new mutation? The 2 major mutations that I described C797S and c-Met are about 40% of the resistance pattern, so there's a lot of other patients that have different patterns of resistance, and it is yet unknown as to whether or not they will benefit/won't benefit or for how long.

TARGETED ONCOLOGY: Were there any unexpected toxicities with this regimen?

Spira: All the safety signals were expected. We knew they were patients having reactions from early on, so those infusion-related reactions are very well dealt with, and most patients do better after the first dose. The other toxicity seen is classical EGFR toxicity, so that was seen, known and expected, and this was carefully monitored. While it's not as easy as taking single agent, either osimertinib or lazertinib, in general, it was well tolerated, and patients did fine with it.

TARGETED ONCOLOGY: What are the next steps of this research?

Spira: The next step is to figure out where this will fall. More patients, what are the resistance patterns, and then figuring out what is the best approach. Is to continue to look at relapsed/refractory patients, or is it to look in the frontline setting? The real question is, can you give this combination to frontline patients in lieu of osimertinib and then increase the duration of response and the durability of a response. That's tougher to look at because the timeframes are much longer. It's an IV and oral versus an oral medicine, which makes patients perhaps a little bit more reticent to participate. Nevertheless, I think those are the 2 big areas. Where does it fall in the second line therapy? Where does it go for the long term for that? Are the specific mutations to target, or is it going to be all comers and then in the frontline? Secondarily, there's some excitement for this drug in the EGFR exon 20 population. There was no data presented at ESMO this year, but we know they've explored breakthrough designation for that based on supplementary results. That's a completely separate area of interest for there is no FDA-approved drug currently.

Reference

Cho BC, Lee KH, Cho EK, et al. Amivantamab (JNJ-61186372), an EGFR-MET bispecific antibody, in combination with lazertinib, a 3rd-generation EGFR tyrosine kinase inhibitor, in advanced EGFR-mutant NSCLC. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract 1258O.