Managing Adverse Events in EGFR Exon 20 Insertion–Targeted Therapies for NSCLC

Millie S. Das, MD

MODERATOR

Clinical Associate Professor, Department of Medicine

Division of Oncology

Stanford Medicine

Palo Alto, CA

EVENT REGION California

PARTICIPANT LIST Deepti Behl, MD | Yelena Krijanovski, MD | Gigi Chen, MD | Sam S. Yeh, MD | Merin M. Stephen, MD | Andrea G. Edwards, MD

CASE SUMMARY

A 64-year-old Asian woman presented with persistent dry cough and mild progressive dyspnea over the past month, with unintentional weight loss of 8 lb over the past 4 months. She had a medical history of hypertension and hypercholesterolemia and is a never-smoker. Right lower lobe (RLL) auscultation revealed decreased breath sounds. Her ECOG performance status was 1. A CT scan showed a 3.5-cm mass in RLL, small right pleural effusion with nodularity as well as mediastinal lymph nodes. PET/CT showed multiple bone metastases, including vertebrae and left scapula.

Brain MRI was negative for brain metastasis. Mediastinal node endobronchial ultrasound led to diagnosis of non–small cell lung cancer (NSCLC); TTF1+ adenocarcinoma; stage IVB. She was started on chemotherapy doublet (cisplatin and pemetrexed). Tissue next-generation sequencing showed EGFR exon 20 insertion mutation (V769_D770insASV). Four months after initiation of chemotherapy (with initial partial response), she reported worsening back pain and shortness of breath. A CT scan showed disease progression, and repeat brain MRI showed no metastases.

DISCUSSION QUESTION

• What factors besides efficacy play a role in your choice of therapy?

DAS: Why did most of you choose amivantamab-vmjw [Rybrevant], and what factors are coming into play here?

BEHL: I chose amivantamab because [although] the first time, [the majority] are going to get some infusion reaction, we’ve learned to manage it [Table 1¹]. After that, it tends to be a pretty tolerable drug.

It is an infusion, so the patient has to come in, but other than the infusion reaction, I have not found it too troublesome. It has the EGFR [tyrosine kinase inhibitor (TKI)] adverse events [AEs] of skin toxicity and diarrhea, but overall, my impression so far has been favorable.

DAS: For those of you who chose mobocertinib [Exkivity]…it is a pill, so it may be a more attractive option for patients who prefer an oral therapy. When we see these patients, we have to discuss both of these options. They’re both FDA approved against a specific mutation, but they have some differences. It’s about having a discussion with the patient, and it depends on your [own] comfort and experience. We [at Stanford Medicine] had experience using amivantamab in the clinical trial setting, so that has tended to be our preferred option. Amivantamab was approved a few months before mobocertinib.^2,3

KRIJANOVSKI: I agree with Dr Behl [concerning amivantamab].… As soon as you can get through the infusion reactions, it should be easy. It is IV [intravenous], so the patient has to travel to the infusion center, compared with [mobocertinib], but it is well tolerated and has a high response rate.¹

CHEN: I’ve had challenges with the skin AEs with [amivantamab]. In particular, the rash and the scalp lesions from the acne rash…and also the paronychias…have been challenging. A couple of my patients have been followed by dermatology. They’d be on doxycycline, some of them have gotten UV treatments and soaks, but that is all quite challenging. I dose reduced, but still, I think that’s the hardest part to manage.

DAS: It’s pretty common to comanage with dermatology, if you can. I typically would give something like doxycycline or a topical steroid. If patients are not responding, then [I have a] very low threshold with some of these patients to see a dermatologist, and typically try to comanage. Before we were using osimertinib [Tagrisso], we saw a higher incidence of some of the rash and skin changes with the earlier-generation EGFR TKIs.⁴ I have noticed that the dermatologic toxicity with amivantamab is similar to the earlier-generation TKIs. The infusion reaction is unique.

When I first started using this drug, and all my patients were getting these infusion reactions, it was not a typical reaction for most lung cancer drugs. I’ve had some patients tell me they thought they were going to die. Is this something that worries you about the drug? It sounds like you’re all OK with it, and you’ve been able to counsel patients about that. Since you treat other cancers, is this something that you see with other drugs?

CHEN: We certainly get this infusion reaction with other drugs. It is very common to see it with amivantamab, but our infusion nurses are able to take care of it. They’re familiar with the management of the infusion reaction.

YEH: I don’t have experience with this drug. But this reminds me of the cetuximab [Erbitux] reaction with a rash.

DAS: Yes, it is similar.

YEH: It sounds more like a cetuximab infusion reaction than rituximab [Rituxan]. With rituximab, you don’t see rash. That’s how I see it, but I haven’t used it.

DAS: It’s a bispecific antibody, so it’s similar to cetuximab. I remember giving cetuximab to patients with lung cancer back in the day, and I think you’re right. It’s similar.

STEPHEN: It also sounds like daratumumab [Darzalex], another antibody, in multiple myeloma…where sometimes, the pharmacists have advised splitting the dose over 2 days to help with the reaction.⁵

DAS: That’s what you do for this drug, so it’s a similar concept with these antibody drugs.⁶ It is split over 2 days, [which] means extra visits for the patients [because of] this infusion reaction concern.

STEPHEN: And you only do that for the first time, and then you don’t have to split it.

DAS: Yes. It’s only the first time you give it.

DISCUSSION QUESTION

• What are the practical considerations of using amivantamab and mobocertinib?

DAS: Amivantamab is a bispecific antibody targeting EGFR and MET, [whereas] mobocertinib is a TKI. Amivantamab is given IV vs mobocertinib given orally. We talked about the split dosing of amivantamab for that infusion reaction.

There is an infusion in week 1, on day 1 and 2, and then it is administered every 2 weeks, starting at week 5. Whereas mobocertinib is given 160 mg orally daily, with or without food.⁶ The major difference is mobocertinib tends to be more associated with diarrhea, and amivantamab more with the infusion reaction.

The warnings and precautions are a little bit different between the 2 drugs. [They include] the infusion reaction for amivantamab, interstitial lung disease/pneumonitis for both drugs, ocular toxicities specific to amivantamab, and for mobocertinib, there is QTc prolongation and cardiac toxicity.^6,7 I recently started a patient on mobocertinib. It was recommended to get a baseline ECG, similar to what we get for patients starting on osimertinib. There wasn’t clear guidance on the regularity of the need for continuing to get ECGs.

EDWARDS: What type of ocular toxicity [is associated with amivantamab], and should a patient have eye exams routinely?

DAS: If they had an ocular toxicity, I would send them to see an ophthalmologist for a formal eye exam. It’s a much rarer AE, and it’s not something that we have to think about too often.

Typically, especially with these drugs that haven’t been around for that long, if we’re seeing these kinds of toxicities, I do reach out to the companies for guidance.

I personally have not seen this, and I don’t know the specific type of ocular toxicity. I would have a low threshold to send these patients for a formal ophthalmologic exam. The hope is that [it’s similar to] the ocular toxicities that we see with some of our other drugs, [where] it’s usually short, self-limited, and it goes away. I’m not sure if that’s the case with amivantamab.

DISCUSSION QUESTION

• How should patients with EGFR exon 20 insertion–positive NSCLC be counseled about targeted therapy?

YEH: The main thing is that one is oral and the other is IV. We’ll see what the patient prefers. I go over the infusion reaction, the rash, and see what the patient prefers. A lot of time, it has to do with the hospital formulary, what the preferred drug is, and what your internal pathway recommends.

DAS: We don’t have specific pathways, but I know a lot of institutions have pathways. That will absolutely guide your decisions. I always think, if I were the patient, which one would I want?

It’s hard because they’re different drugs. There’s a bias toward oral [therapies] for patients, but I try to remind patients that just because it’s a pill doesn’t mean that it doesn’t have AEs.

BEHL: It’s also about logistics. Coming in for infusion is not that easy for patients who live far away.

KRIJANOVSKI: Have you been needing to do dose reductions of oral mobocertinib?

DAS: I haven’t had to dose reduce yet, but I might. I have only had 2 patients [on mobocertinib]. We’re premedicating these patients for the diarrhea, because it’s going to happen, like the infusion reaction for the amivantamab [Table 2⁸].

I am typically giving these patients loperamide [Imodium] to take with their mobocertinib, to try to prevent that diarrhea. I haven’t had to dose reduce, but there are dose reduction guidelines. Over 90% of these patients are going to get it, so I tell them to take loperamide with it in the beginning and see how it goes.

_REFERENCES

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_{2. FDA grants accelerated approval to amivantamab-vmjw for metastatic non-small cell lung cancer. FDA. May 21, 2021. Accessed August 31, 2023. https://tinyurl.com/94mmduz6}

_{3. FDA grants accelerated approval to mobocertinib for metastatic non-small cell lung cancer with EGFR exon 20 insertion mutations. FDA. September 16, 2021. Accessed August 31, 2023. https://tinyurl.com/y594zmws}

_{4. Melosky B, Leighl NB, Rothenstein J, Sangha R, Stewart D, Papp K. Management of EGFR TKI-induced dermatologic adverse events. Curr Oncol. 2015;22(2):123-132. doi:10.3747/co.22.2430}

_{5. Darzalex. Prescribing information. Janssen Biotech, Inc; 2022. Accessed August 30, 2023. https://tinyurl.com/ca8rdyn2}

_{6. Rybrevant. Prescribing information. Janssen Biotech, Inc; 2021. Accessed August 30, 2023. https://tinyurl.com/36232u83}

_{7. Exkivity. Prescribing information. Takeda Pharmaceuticals; 2021. Accessed August 30, 2023. https://tinyurl.com/5n6e39xe}

_{8. 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}