Areas of Concern in Using Amivantamab and Mobocertinib in EGFR Exon 20+ NSCLC

Joshua K. Sabari, MD

Assistant Professor, Department of Medicine

NYU Grossman School of Medicine

Director, High Reliability Organization Initiatives

Perlmutter Cancer Center

New York, NY

DISCUSSION QUESTION

• Please discuss your answer to the polling question.

JOSHUA K. SABARI, MD: Very interesting, 22% said mobocertinib [Exkivity] and 78% said amivantamab [Rybrevant]. Both of these answers are correct. Mobocertinib is an EGFR/HER2 exon 20 TKI [tyrosine kinase inhibitor]. Amivantamab is an EGFR c-MET bispecific antibody.

NAGASHREE SEETHARAMU, MD: [I chose] mobocertinib. It’s an oral medication. I know how to manage it. I’ve always done it that way. Patients will need both these agents in their lifetime. Neither of these drugs have very prolonged duration of response. I’m used to mobocertinib followed by amivantamab, and also giving patients a break from intravenous [IV] therapies. There’s no head-to-head comparison between the 2. I’ve gotten very comfortable with managing the adverse events of mobocertinib. And neither of them has CNS [central nervous system] penetration.

LAN MO, MD: I chose amivantamab because we know [for the] 2 medications, the overall response is similar, around 40%, and PFS [progression-free survival] is also similar….^1,2 I use amivantamab; you just have to be careful…[due to] infusion reactions.

ILYA BLOKH, MD: They’re both reasonable to use. It’s a matter of oral versus IV. I haven’t used either of them. I just chose amivantamab. I thought it had a higher objective response rate [ORR], but I don’t have experience with it.

KEVIN SING, MD: I chose amivantamab. I haven’t used either. As others have mentioned, at least the studies show slightly higher [ORR by blinded independent review though] you can’t compare 1 [study] versus the other. [There are also] adherence issues [for IV versus oral]. I would prefer knowing when my patient is getting certain drugs.

DISCUSSION QUESTION

• What is your reaction to the data for amivantamab in the phase 1 CHRYSALIS study (NCT02609776)?

SABARI: What’s your reaction to the CHRYSALIS data, and what stood out to you in terms of efficacy and safety?

PAULINE LAU, MD: The disease control rate [of 74%] was amazing as demonstrated by the waterfall plot.¹ The median overall survival [of 22.8 months], [though] immature for this group of patients in the second line…was extremely inspiring.

JOSHUA STRAUSS, MD: Whenever you review a toxicity profile, you have to review it in the context of what else you have available. Patients don’t have a lot of options. They don’t respond well to chemotherapy [or] typical EGFR therapy. [Considering] the efficacy, the toxicities are manageable. You have infusion reactions so you have to watch these patients carefully, but these are not things that would dissuade me from using this drug.

SING: It’s a good performance for a second-line agent, giving us quite a bit of median PFS and a good response giving our patients months and maybe a year or so more disease control and ability to prolong their lives.

DISCUSSION QUESTION

• What is your reaction to the data for mobocertinib in the phase 1/2 trial (NCT02716116)?

SABARI: What’s your reaction to these data? I’ll start with Dr Seetharamu, because you said you use this in clinical practice.

SEETHARAMU: I’m quite happy with the responses. As [for] toxicity, once you start using these agents, you get into the practice of educating patients and proactively starting antidiarrheal medications. Skin and GI [gastrointestinal] toxicity are foremost, and I proactively start managing these patients’ toxicities. Most of my patients take loperamide [Imodium] every morning, regardless of whether they have diarrhea or not. I found that extremely helpful. [I use] dose management, escalating up in some patients, especially [those] with poor performance status or who are fragile. [This is also helpful for] patients who have had prior cutaneous or GI toxicity with other TKIs [such as] osimertinib [Tagrisso] that they might have used in the past. With these strategies, I’ve been able to manage patients’ toxicities for a longer time.

SABARI: That’s a great point on dose reduction. [Although] 160 mg is the standard dose, dose reduction to 120 mg is very common and was commonly done on the study.² We don’t have clear durability [data] at that dose, but I do think it’s important to dose reduce patients who are having toxicity.

ANITA GUL, MD: To me, both of these drugs are good options. I personally haven’t used [either] of them, so if I would have a chance, I would discuss toxicities with the patient. There is a slightly different toxicity profile. I don’t see a lot of difference in efficacy. They are both are good drugs and [I would] see…whether they like to come in for infusion [for amivantamab] versus having severe diarrhea and rash [with oral mobocertinib].

SABARI: I agree. It comes down to a discussion with your patient. Just because a therapy is oral does not mean that it’s easier. I have started patients on mobocertinib in the frontline setting. You do have to manage them closely [for diarrhea] and monitor [electrolytes]. They need IV hydration. You need dose holds.

Similarly, I’ve started patients on amivantamab upfront. You have to monitor for the infusion-related reaction. You have to talk to patients about the weekly infusions for the first 4 or 5 weeks, followed by [every 2 weeks]. It is a discussion with patients on managing their expectations.

LAU: [For] mobocertinib, in the patients’ selection criteria, a good proportion of them had CNS/brain metastases. Did the study for amivantamab also treat patients with brain metastases? I wonder if that could also be a point to consider.

SABARI: For the mobocertinib study, about 35% had prior treated brain metastases.² In amivantamab, I believe the number was 25% who had prior treated brain metastases.¹ No patients went on either of these studies with active, untreated brain metastases. Neither amivantamab or mobocertinib, to my knowledge, have good CNS penetration. If you do have a patient in the second-line setting with brain metastases, there are active agents being studied, BLU-451 and ORIC-114, that preclinically do have CNS penetration. CLN-081 potentially has CNS penetration. But if you’re going to use amivantamab or mobocertinib, consider radiation of the brain metastases up front.

LAU: If they get radiation [therapy], one is a bispecific antibody, and one is a targeted agent. Would the reaction be different with the CNS toxicity?

SABARI: We don’t see CNS toxicity with either one of these agents. For GammaKnife stereotactic radiosurgery, these are 1-day procedures. We don’t see much complication. For whole-brain radiation, you may want to hold both the TKI or the bispecific because of other systemic adverse events or symptoms patients are going to have. But we moved away from whole-brain radiation, particularly in this patient population. I have no concern giving either the bispecific amivantamab or the TKI mobocertinib in a patient who’s undergoing radiation or post radiation to the brain. The key teaching point here is: don’t allow patients to go on these agents with active, untreated CNS disease. These drugs do not have good CNS penetration.

_References:

_{1. 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}

_{2. Zhou C, Ramalingam SS, Kim TM, et al. Treatment outcomes and safety of mobocertinib in platinum-pretreated patients with EGFR exon 20 insertion-positive metastatic non-small cell lung cancer: a phase 1/2 open-label nonrandomized clinical trial. JAMA Oncol. 2021;7(12):e214761. doi:10.1001/jamaoncol.2021.4761}