Supportive Care Reduces AEs With MARIPOSA Regimen in EGFR+ NSCLC

Treatment for EGFR-mutated advanced non–small cell lung cancer (NSCLC) has advanced over the past several years with the introduction of next-generation targeted therapies that are more effective at reaching tumor cells and overcoming common resistance mechanisms. The phase 3 MARIPOSA trial (NCT04487080) introduced a combination EGFR-targeting regimen and compared it with the standard-of-care osimertinib (Tagrisso). In a live Case-Based Roundtable event in Detroit, Michigan, Shirish M. Gadgeel, MD, division head for Hematology/Oncology and associate director for Patient Experience and Clinical Care at Henry Ford Health, discussed how this combination comes with particular adverse events (AEs) that led to additional studies on supportive care. During the event, Gadgeel shed light on the typical timing of toxicities and how supportive care regimens can dramatically reduce AEs that could otherwise require dose modification or interruption.

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CASE SUMMARY

• A 55-year-old construction worker presented to their primary care physician with a dry cough, fatigue, and sporadic headaches​.
• Medical history: hypertension controlled on candesartan​
• Prior smoking history​
• Initial physical examination:blood pressure 148/70; decreased breath sounds (left lower lobe); weight 176 lb​
• ECOG performance status: 1
• Chest x-ray revealed patchy consolidation in left upper lobe​
• CT scan of chest, abdomen, and pelvis revealed 5-cm mass in left upper lobe and enlarged lymph nodes
• Patient referred to oncologist on suspicion of malignancy
• Brain MRI:demonstrates 10-mm right parietal mass ​
• Pathology:adenocarcinoma​
• Immunohistochemistry: positive for CK7 and TTF-1​
• Molecular profile: EGFRL858R mutation, PD-L1 25%​
• The patient wants to engage in shared decision-making with physician and multidisciplinary team.

Targeted Oncology: What are the key tolerability concerns with the amivantamab (Rybrevant) plus lazertinib (Lazcluze) regimen?

Shirish M. Gadgeel, MD: The biggest issue with the combination of amivantamab/lazertinib is the toxicity, and particularly the EGFR toxicities. Even though most of them are grade 1 or 2, they're much more than [those of] single-agent osimertinib. I don't think that’s a surprise. What is interesting to know is it is a matter of getting the patient through the initial period of treatment. Most of the toxicities are observed in the first 4 months.¹ There is less toxicity later on. This is partly because some of the patients do come off treatment and [receive] dose reductions. But it is a matter of how you can manage these toxicities in the initial months, and there's a possibility that once you've reached a certain plateau after a few months, you may not experience as severe toxicity.

The other important thing is the [EGFR] AEs. About 10% of the patients on osimertinib alone had venous thromboembolism [vs 37% with amivantamab/lazertinib].² There are data to suggest with certain subsets like patients with ALK, a little more than EGFR, have a greater propensity to develop venous thromboembolisms.³ If you have patients with brain metastases or their mobility is not that great, I would consider starting apixaban [Eliquis] in many of the patients with targetable alteration at 2.5 mg twice daily. Clearly, it is greater with the combination; a little over one-third of the patients develop venous thromboembolism. What is interesting is this is not necessarily seen when you give amivantamab alone. This is about giving the combination, and I'm not sure what exactly the mechanism is.

One can be very optimistic and say that [the cause is the] amount of tumor killed that [results in] release of intracellular vesicles. I don't know if that's the case, but it is now recommended that you start them on anticoagulation if you're going to start amivantamab/lazertinib and you want to start right from day 1. But they saw it in the first 4 months, so you can take the patient off the anticoagulation as long as they have not developed a deep vein thrombosis after 4 months of using treatment with an anticoagulant.

What approaches are there to managing infusion reactions with amivantamab?

With the SKIPPirr [NCT05663866] protocol, the infusion reaction goes down, and they still get something, but it's never serious. They looked at different ways of managing infusion reactions. They only treated 6 patients [per prophylactic approach] and figured out in which arm they had the least amount of infusion reaction. It was the dexamethasone: they gave 8 mg twice daily for 2 days before the first infusion. They still got dexamethasone on the day of the infusion. There was no need after the infusion, though you do it on day 1 and 2, and they found that it had reduced with prophylactic measures from 61.4%—[in my experience] everybody gets infusion reaction if you don't use dexamethasone—but if you use dexamethasone, it’s not just that it goes down [to 22.5%], but you [also] don't see severe reactions.⁴ If you don't give dexamethasone, some patients can develop significant hypotension, shortness of breath, and flushing, and it can be a source of concern.

With this regimen, one important thing to remember, and this is something I learned the hard way when we participated in the MARIPOSA study: if you hold amivantamab—and my cutoff is anything more than 4 weeks—you have to do this again. You have to give the amivantamab infusion over 2 days and do the SKIPPirr protocol, because you can still get infusion reactions. In my patient who I treated on the MARIPOSA trial, that patient had also developed a pretty significant scalp reaction. We held the drug for something like 6 to 8 weeks, and then we dosed her, and [we did not] redo the [prophylaxis], and then the patient developed a pretty significant infusion reaction. Remember that not only [should] do you do this for cycle 1 day 1, but you also do this for patients in whom you give a break of anything.

What research has been done on reducing dermatologic toxicities?

The COCOON trial [NCT06120140] randomly assigned patients who were getting amivantamab plus lazertinib to enhanced dermatologic management or standard dermatologic management. What this involved is starting doxycycline from day 1, instructing patients to use sunscreen, [using] chlorhexidine for nails, and then ceramide-based moisturizer, and you apply it all over the body. In my experience, even if you do that, patients get reactions. In the COCOON trial, they did see a reduction in the dermatologic AEs from 76% to 38% and also saw a reduction in grade 3.⁵ Frankly, I feel that as soon as you start seeing toxicity, it is best to either dose reduce or hold the drug. You continue [to see] skin toxicity, but I think it is much better to be proactive. Once a patient develops pretty significant rash, it is extremely difficult to catch up on the rash and then you end up holding the drug for a long time. I feel that is good to do all the skin management but be very liberal to dose reduce or hold the drug.

The scalp is the biggest issue. You do see skin rash like you see with erlotinib [Tarceva] or afatinib [Gilotrif], but the scalp reaction is quite common, and I will tell patients very quickly to use steroid shampoos. As soon as I see any evidence, I will tell them to use steroid shampoos to manage the scalp rash. Some patients develop mouth sores; you can develop mouth sores with osimertinib alone, but I feel that the combination does cause more mouth sores than what I see with single agent. They saw not only overall reduction in dermatologic toxicities, but they also saw in rash on the body, scalp reaction, and paronychia.⁵

There were still dose modifications or dose interruptions needed, but it did lead to less dose interruptions and less dose reductions. What is interesting, at least in the COCOON trial, only 4% of the patients discontinued even with standard skin management, and 1% in patients with enhanced [management]. I will say that my dose interruption rate is somewhat higher than 16% even with the COCOON regimen…with the limited number of patients I have treated.

DISCLOSURES: Gadgeel previously reported institutional research funding from Amgen, Astellas Pharma, AstraZeneca, BioMed Valley Discoveries, Blueprint Medicines, Calithera Biosciences, Genentech/Roche, Daiichi Sankyo, Debiopharm Group, Dragonfly Therapeutics, eFFECTOR Therapeutics, Elevation Oncology, Erasca Inc., Helsinn Therapeutics, I‐Mab, Incyte, InventisBio, Janssen Oncology, Merck, Mirati Therapeutics, Nektar, Numab, Pfizer, Regeneron, Turning Point Therapeutics, Verastem, and Ymabs Therapeutics; personal/consulting or advisory fees from AbbVie, Amgen, Arcus Biosciences, Astellas Pharma, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly & Company, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, I‐MAB, Janssen Oncology, Merck, Mirati Therapeutics, Novartis, Nuvation Bio, Pfizer, Regeneron, and Takeda Oncology; honoraria from Merck; support for other professional activities from AstraZeneca; and travel support from Merck and Mirati Therapeutics.

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REFERENCES:

1. Yang JC-H, Kim YJ, Lee S-H, et al. Amivantamab plus lazertinib vs osimertinib in first-line (1L) EGFR-mutant (EGFRm) advanced NSCLC: Final overall survival (OS) from the phase III MARIPOSA study. J Thorac Oncol. 2025;20(3):S6-S8. doi:10.1016/S1556-0864(25)00199-6

2. Cho BC, Lu S, Felip E, et al. Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC. N Engl J Med. 2024;391(16):1486-1498. doi:10.1056/NEJMoa2403614

3. Roopkumar J, Poudel SK, Gervaso L, et al. Risk of thromboembolism in patients with ALK- and EGFR-mutant lung cancer: A cohort study. J Thromb Haemost. 2021;19(3):822-829. doi:10.1111/jth.1521

4. Paz-Ares LG, Spira AI, Han J-Y, et al. Preventing infusion-related reactions with intravenous amivantamab: Updated results from SKIPPirr, a phase II study. Ann Oncol. 2024;35(suppl 2):S812. doi:10.1016/j.annonc.2024.08.1326

5. Girard N, Li W, Spira A, et al. Preventing moderate to severe dermatologic adverse events in first-line EGFR-mutant advanced NSCLC treated with amivantamab plus lazertinib: early success of the COCOON trial. J Thorac Oncol. 2025;20(3):S14-S16. doi:10.1016/S1556-0864(25)00205-9