Exploring Targeted Treatments and Their AEs in EGFR-Mutated NSCLC

Alexander I. Spira, MD, PhD (Moderator)

Codirector

Virginia Cancer Specialists Research Institute

Director, Thoracic and Phase I Program

Clinical Assistant Professor, Johns Hopkins Medicine

Fairfax, VA

DISCUSSION QUESTIONS

• Have you used amivantamab (Rybrevant) plus lazertinib (Lazcluze) as first-line therapy on or off a clinical trial?
• Do you have any premedication protocols?

Nataliya Melnyk, MD: I have not used the combination. I just started [amivantamab] in the second line, not the first line.

Daya S. Sharma, MD: I have not used it in the first line. If I have to use amivantamab, I would rather use it in the second line with chemotherapy.

Alexander I. Spira, MD, PhD: Are there any issues that you have had in the second line, if no one here has given it in a frontline scenario?

Melnyk: An issue is skin toxicity. I was able to get the drug, but skin toxicity is significant. It’s a bit of a challenge to manage.

M. Kelly Hagan, MD: The infusion reaction [is an issue].... I don’t know how many people are aware that you’re not supposed to give it through the port-a-cath for the first cycle so that if they have an infusion reaction, you can give fluids. If there’s still drug in the line, you’re giving them even more. I had to point out to my group to try to give the first dose, if possible, through a peripheral line. Think about doing it on day 2, maybe even the next dose, before you use it in the port. At a talk I went to, Corey Langer, MD, stressed that as well….

Spira: You’re right, you have to deal with what you have to do for patients’ intravenous access. The reason it was done is because of that exact reason. The subcutaneous form has less of an infusion-related reaction. Has anyone here given premedication protocols for amivantamab?

Hagan: It’s built into our computer system with the steroids, antihistamines, etc.

Spira: The original CHRYSALIS study [NCT02609776] did not give any patients pre-medications. However, the SKIPPirr study [NCT05663866] looked at giving patients premedication with dexamethasone several days before, as well as the morning of [treatment], and it does decrease the risk of infusion reactions.¹

So there are some data that pre-medication will prevent it. Then, the subcutaneous amivantamab will make up for that once that is approved, but that’s not currently approved.

Melnyk: I just had experience with [a male patient given amivantamab]. Luckily, he didn’t have a reaction, and he doesn’t have any other symptoms. He feels well on the treatment besides the skin reaction and rash, which I’m managing. I did reduce the dose. He’s 84 years old, so maybe that’s helping in addition.

Raj Manchandani, MD: How was the experience with pneumonitis? That’s another adverse event [AE] that has been reported in the trials. How bad was it, and how soon did patients notice the pneumonitis?

Spira: Pneumonitis is seen, but it’s relatively rare. It can happen at any point during the regimen. It is still not that common—not nearly as common as antibody-drug conjugates. But I’ve given a lot of [amivantamab], and some patients have had pneumonitis, but it’s rare.

DISCUSSION QUESTIONS

• What are your thoughts of the MARIPOSA data (NCT04487080)?²
  • Which data points stand out to you?
  • How does the data impact your first-line treatment consideration?
  • What impact do these data have on treatment sequencing?

Spira: What do you think about the data? Is it going to make you think about using amivantamab plus lazertinib more often?

Ligeng Tian, MD, PhD: The overall survival was impressive. That changes how I look at this. However, some of the toxicity can be a barrier. I look forward to using it when the subcutaneous version comes out.

Spira: What have you heard about the subcutaneous version that makes you excited about it?

Tian: Less infusion reactions and less of—not sure if it’s true—but the rash apparently and skin toxicities. Just a quick shot, go home with a pill. That’s more appealing to the patients and hopefully avoids hospital admission.

Jose A. Mendoza, MD: It seems like there may be less venous thromboembolism than with the intravenous regimen.³ The other thing is that there may be some improvement in overall survival as well. The question is, why that may be? The subcutaneous formulation may be favorable to a more steady-state kind of action of the medication, so I share that enthusiasm. I want that to be available by the time I have to face this issue with the patient.

Arun Bhandari, MD: We don’t know the comparison with chemotherapy plus osimertinib [Tagrisso] vs the MARIPOSA regimen—and we know [osimertinib] is easy to give. You give 4 cycles of chemotherapy, although in the trial, they give pemetrexed along with osimertinib. I generally stop pemetrexed and continue single-agent osimertinib to make patients’ lives easier.

Spira: The FLAURA2 [NCT04035486] investigators gave patients carboplatin/pemetrexed plus osimertinib vs osimertinib, and then they stayed on pemetrexed plus osimertinib as maintenance thereafter.⁴ How do you compare FLAURA2 vs MARIPOSA? I don’t think we’re ever going to see a direct comparison. That study is not planned on being done, so we’re just going to be comparing anecdotal data.

Sharma: Osimertinib and chemotherapy is easier to go with compared with amivantamab/lazertinib. So I would keep amivantamab in the second line.

Spira: Why do you think it’s easier?

Sharma: Because there’s no infusion reaction. If a subcutaneous version is available for amivantamab, then I will do that, but otherwise, I prefer to use osimertinib plus chemotherapy.

Spira: We talked a lot about the infusion reaction, and I hear you loud and clear, but it typically only happens with the first dose. The first dose is split over 2 days, and you typically only get the infusion reaction that first day, and then not after that. I agree that the subcutaneous [formulation] is going to be easier for multiple issues, including limiting the infusion reaction on the first day.

How do people compare the AE profile of the 2 regimens?

Qiwei Gai, MD, PhD: Both groups of data came up recently. It’s going to be very difficult to do a comparison…. Either one will be reasonable for me to do.

Tian: I wonder if the TP53 [subgroup] in the MARIPOSA data makes people do anything different. It’s not necessarily that it overcomes the TP53 mutation, but it seems with MARIPOSA that it’s improving in this population.

Manchandani: With the MARIPOSA trial, was there a subset analysis of other high-risk features, like TP53 mutation or liver metastases or high circulating tumor DNA burden? Were there any data on those to help tease out if the data is strong enough in higher-risk patients?

Spira: If you look at all 4 of those high-risk categories, the combination therapy did better on liver metastases, brain metastases, TP53, and circulating tumor DNA. All those did better on the combination.²

[In terms of] treatment sequencing…you can look at it both ways because you can give carboplatin/pemetrexed plus osimertinib frontline and then save amivantamab for the second line. Although, the MARIPOSA2 approval is with chemotherapy in the second-line setting. Or you could do vice versa, where you give amivantamab first line and then give osimertinib/carboplatin/pemetrexed in the second line.

Disclosures: Dr. Spira reports serving in a leadership role at NEXT Oncology Virginia; holding stock in Eli Lilly; receiving honoraria from CytomX Therapeutics, AstraZeneca/MedImmune, Merck, Takeda, Amgen, Janssen, Novartis, Bristol Myers Squibb, and Bayer; serving in a consulting or advisory role for Incyte, Amgen, Novartis, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Takeda, Janssen Research & Development, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Regeneron, Array BioPharma, AstraZeneca/MedImmune, Merck, Bristol Myers Squibb, and Blueprint Medicines; and receiving research funding from LAM Therapeutics, Regeneron, Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, NewLink Genetics, Incyte, AbbVie, Ignyta, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone Bio, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen, Mirati Therapeutics, Rubius, Synthekine, Mersana, Blueprint Medicines, Alkermes, and Revolution Medicines.

_References:

_{1. Paz-Ares LG, Spira AI, Han JY, et al. 1269P Preventing infusion-related reactions with intravenous amivantamab: Updated results from SKIPPirr, a phase II study. Annal Oncol. 2024;35(2):S812. doi:10.1016/j.annonc.2024.08.1326}

_{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. Leighl NB, Akamatsu H, Lim SM, et al. Subcutaneous versus intravenous amivantamab, both in combination with lazertinib, in refractory epidermal growth factor receptor-mutated non-small cell lung cancer: primary results from the phase III PALOMA-3 study. J Clin Oncol. 2024;42(30):3593-3605. doi:10.1200/JCO.24.01001}

_{4. Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2023;389(21):1935-1948. doi:10.1056/NEJMoa2306434}