Therapy With Bispecific Antibody for EGFR Exon 20 Insertion–Mutated NSCLC
During a Targeted Oncology case-based roundtable event, Christine Bestvina, MD, discussed the outcomes of clinical trials of the EGFR exon 20-targeted agents amivantamab and mobocertinib with participants. This is the second of 2 articles based on this event.
CHRISTINE BESTVINA, MD: What is your reaction to the efficacy data and adverse event [AE] profile [of amivantamab]?
MURUGAVEL MUTHUSAMY, MD: I don’t see anything [concerning] other than antibody allergic reactions, and EGFR [therapy-related] rash. We’re all used to this kind of adverse reaction facing cetuximab [Erbitux] and others. Efficacy seems to be interesting; I think it is OK safety-wise.
BESTVINA: So you are not scared away by the [high] rate of infusion reaction.
MUTHUSAMY: We’ll see what others think, but my feeling is I’m OK with that. We can deal with that.
KARIM ANWAR, MD: I think we all are used to seeing infusion reactions with different drugs.The only [issue] is the deaths that were in the trial; what were they related to?
BESTVINA: I don’t have that information, and so whenever we see deaths on clinical trials, it always does make me pause, as well. Is this death due to progression that was misclassified, or was it an AE-related [death]? I don’t recall [the attributed cause of each death] offhand. It’s a good question.
ISOKEN KOKO, MD: With regard to efficacy, considering that the options for this group of patients are limited, I think the response rate is quite remarkable.
BESTVINA: So, you are happy with the 40% response rate?1
KOKO: Yes, considering there’s nothing else, other than second-line chemotherapy.
BESTVINA: Right, and nobody’s excited about docetaxel.
MELHEM JABBOUR, MD: When you have those allergic reactions or infusion reactions—normally with other [drugs], we’ll hold, we’ll infuse slower, [and ask if] we have something to give premedication. It’s like any other infusion reaction, is that correct?
BESTVINA: That’s exactly right. So, you essentially hold the infusion, you give additional steroids, additional premedications, and then restart the infusion at a slower rate. Almost all [infusion reactions] occur with the first infusion. The rate of infusion reaction goes down substantially with infusion No. 2, and is almost nonexistent by infusion No. 3. So, it is 1, maybe 2 incidents, and then after that, that infusion reaction goes away.
ALKARIM TAJUDDIN, MD: For the response to the rash, should doxycycline [be used] just like [with] cetuximab, or other local treatments?
BESTVINA: I believe you can use doxycycline. The majority of those dose interruptions [in the study] were likely related to rash, as well. That’s another way to try to break the cycle with the rash, and local therapies, and so I have found it to be much more manageable than even with earlier-generation EGFR TKIs like erlotinib.
BESTVINA: How do you react to these data on mobocertinib? And how do you view the safety and efficacy?
NISHANT PODDAR, MD: Do you have more information on the population that had the ILD [interstitial lung disease], or pneumonitis? Most likely, the drug was discontinued [in these patients] after such an incident, or the episode of ILD or pneumonitis.
BESTVINA: Correct. So, for the ILD/pneumonitis as well as the cardiomyopathy, the drug was discontinued for these patients. We don’t have a lot of information about underlying characteristics. Did they have a mild ILD that got exacerbated by the drug? ILD at baseline was an exclusion criteria for both trials. So, I think we should be assuming, hopefully correctly, that these patients had good lung architecture at baseline.
MUTHUSAMY: Cardiac toxicity is interesting; [we may be] concerned about it. This drug is oral, which is convenient for the patient. Perhaps safety-wise, ILD seems to be higher than the usual—that of erlotinib [Tarceva] and others in that group of drugs. A 4.3% [rate of ILD] is a little higher than usual, is it not?2
BESTVINA: In one of the earlier classes, it’s reported as between 3% and 5%. Even with osimertinib [Tagrisso] in the trial, the reported rate of pneumonitis was 4%.3 That’s certainly been higher than my clinical experience.
MUTHUSAMY: OK, so I think that will be fine.
PODDAR: Do you have a baseline population characteristic for the ILD or pneumonitis? Was it more of an Asian population that had that, just like in the osimertinib trial, or all those TKI [trials]?
BESTVINA: Yes, it’s a great question, but I do not know that data.
ANWAR: It does look to be more toxic than amivantamab. [About] 20% of patients got grade 3 diarrhea, there’s ILD, and cardiotoxicity.2
BESTVINA: That is definitely 1 interpretation of the data.
When you think about what you’re going to offer your patient, and how you’re counseling them in clinic: amivantamab is intravenous, while mobocertinib is an oral drug. [When looking at] the most common AEs, as well as some of the warnings and precautions—with amivantamab, there was a warning or precaution for ILD as well. There is some ocular toxicity. But, with mobocertinib, we also see the QTc [heart rate-corrected QT interval] prolongation, ILD, and diarrhea.
JABBOUR: Did you ever decrease the dose of mobocertinib, to do three 40 mg pills instead of the 160 mg, and can you adjust the dose for fewer AEs? How do you do with managing AEs in those cases?
BESTVINA: Yes, so with intolerable diarrhea or rash, the dose reduction goes to 120 mg.4 I think the question is, are we seeing the true level of efficacy that we need at that dose-reduced level, and I think some of those data still needs to be borne out. What we instead ended up doing was pushing the anti-diarrheals. So, you have the patient get their loperamide [Imodium] before they even start, and the patient then gets quickly escalated as they need to, even all the way up to tincture of opium. And so we tried to aggressively manage the diarrhea, but it can be very tough. With grade 3 diarrhea, it’s pretty hard to do anything.
RON SHADE, MD: I agree. I think that as much as it’s nice to have an oral agent, I was impressed that the amivantamab did not cause much diarrhea. They both caused rash, but I would rather have an infusion reaction. We can manage that quite easily, and it’s usually just the first [infusion] anyway, rather than having weeks and months of diarrhea. Patients like oral agents, but I think that’s a big difference between the 2.
JABBOUR: I agree.
MUTHUSAMY: There was an intriguing cardiac toxicity of [cardiomyopathy leading to heart failure occurring in 2.7% of patients].2 It’s not seen in the class, except lenvatinib [Lenvima], or sometimes a TKI can cause those. But, [not] the EGFR TKIs.
ANWAR: Another thing that comes up is the ocular toxicity with amivantamab. Now, we are seeing it more and more with drugs; I do not know how significant it was, and what percentage of patients got ocular toxicity with it.
BESTVINA: On the clinical trial, these patients ended up having closer monitoring. It is definitely something to consider though—how you roll it out in the community. Do you have an ophthalmologist who you can work with closely to either monitor for these things, or help treat them if they occur?
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
3. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. N Engl J Med. 2018;378(2):113-125. doi:10.1056/NEJMoa1713137
4. Exkivity. Prescribing information. Takeda Pharmaceutical; 2021. Accessed July 6, 2022. https://bit.ly/3PbPu5B