Prophylactic Approaches Lessen Immune-Related Reactions in NSCLC

Results from the SKIPPirr trial assessed the use of amivantamab plus lazertinib for patients with non–small cell lung cancer.

Immune-related adverse effects (AEs) are a common occurrence with immunotherapy treatment for patients with non–small cell lung cancer (NSCLC). Experts from the Mayo Clinic in Rochester, MN, discussed different prophylactic actions they are able to take in order to help prevent or mitigate them.

The panel was led by Konstantinos Leventakos, MD, PhD, a medical oncologist with a focus in thoracic malignancies. Additional members included Harry Fuentes, MD, consultant and assistant professor; Kadi Studeck, MD, a medical oncologist; Kaushal Parikh, MD, a medical oncologist involved in early therapeutics; Ailsa Luce, PA-C, a physician assistant; Tammy O'Brien, NP, a nurse practitioner; Tassos Dimou, MD, a medical oncologist; and Mohammed Shanshal, MB, BCh, MD, a medical oncologist.

Recent clinical trials involving amivantamab-vmjw (Rybrevant) either intravenously (IV) or subcutaneously plus lazertinib (Lazcluze) have demonstrated valuable insights into these immune-related AEs. Moving forward, the experts discussed how to adapt their strategies to involve the prevention of these AEs.

Leventakos: The phase 2 SKIPPirr study [NCT05663866] looked into 4 different independent prophylactic strategies for patients who were receiving amivantamab and or lazertinib.¹ The prophylactic here had to do mainly with the reactions that this patient had. One was dexamethasone at 4 mg, dexamethasone at 8 mg, montelukast at 10 mg, and methotrexate at 25 mg. They looked into [using] Simon’s 2-stage [design], [and] if there was an infusion reaction in 3 patients or less, then they could [enroll more patients].

The 4 mg of dexamethasone and 25 mg of methotrexate did not pass stage 1 [of enrolling 6 patients]. The montelukast did not make it to stage 2 [of enrolling 10 patients]. The prophylaxis of dexamethasone 8 mg passed both stages, went to the expansion stage, and enrolled 24 additional patients. With dexamethasone prophylaxis, they were able to reduce the amivantamab [immune-related reaction (IRR) rate] by 22.5%. The prophylactic schedule is [to take] 2 days [before] and 1 day before [for] dexamethasone at 8 mg in the morning and in the afternoon, and then in the clinic, you get the amivantamab, and you see how [the IRR rate] went from 67.4% to 22.5%.

At the Mayo Clinic, we are blessed to have the most amazing pharmacists, who have taken all this burden of [dosing], which is huge for the care of the patients, but it's interesting to see how some things can change everything, and you see how dexamethasone decreased a lot of AEs. As a reminder, dexamethasone and the other steroids were found at Mayo Clinic, in case we don't remember that. What are some of the strategies that you have in place to manage IRR? Do we have prophylactic supportive measures in place? How would you implement this 8 mg dexamethasone?

Parikh: We don’t need subcutaneous amivantamab anymore?

Leventakos: It is OK that we have maximized everything that would make it easier for the patient. At least the practice at Mayo Clinic is fully updated. We have been giving amivantamab for a long time. We had the first clinical trial here. We have nailed it so far. Would the SKIPPirr trial bringing the reactions from 67.4% to 22.5% make anybody more comfortable incorporating the amivantamab earlier in our practice? Talking to a practice, who has probably nailed everything that has to do with the infusion reaction so far.

Dimou: There is still a lot of toxicity with amivantamab, and supportive care needs to be given. It’s not just the toxicity, it’s also the supportive care that can overwhelm patients. The antibiotics, creams, and shampoos are a lot. Although it is certainly better with a modified pretreatment in terms of the infusion reaction; that’s one thing--there are many others. I wouldn’t change my approach towards amivantamab to prefer it for the later line, or second-line.

Leventakos: The phase 3 PALOMA-3 trial [NCT05388669] was an open-label, randomized study that looked into subcutaneous amivantamab and lazertinib compared with IV amivantamab.² The subcutaneous amivantamab was given 1600 mg weekly for 4 weeks, then every 2 weeks. The comparator arm has matched dosing but was given through an IV. Prophylactic anticoagulation was recommended in both studies. [The results were] mainly pharmacokinetic but had secondary end points of response rate for low inferiority progression-free survival [PFS] and overall survival [OS].

We see that the pharmacokinetics were good. When it comes to efficacy, we have the results that showed that the subcutaneous duration of response was higher than with the IV. PFS was higher, with a good HR. Everybody was a little surprised by that because they went from low inferiority to something that showed that things were even better. When it comes to the safety issues with IRRs, it went down from 66% to 13%, with a huge increase in grade 3 or higher [AEs]. At the median follow-up of 7 months, [the trial] had met both co-primary end points of pharmacokinetics.

There is another phase 2 trial, the COCOON trial [NCT06120140], that looked into dermatologic management with first-line [amivantamab plus lazertinib].³ That speaks to what Dr Dimou said: that it's not only the IRRs, but all the dermatologic [AEs]. We will be working on that. One practical consideration of amivantamab is that we always remember the most common AEs. There are the IRRs in everything that has to do with EGFR. There are warnings and precautions for IRRs, interstitial disease or pneumonitis, dermatologic AEs, ocular toxicity, and [embryonal-fetal toxicity]. How does the team think that the proactive strategies for managing toxicities are for amivantamab?

Shanshal: I can commend that. It’s very important to maximize it more, especially with the PFS and OS benefits in this case. If you look at the way that it’s given, you start with a low dose and then you [increase] the dosing. Minimizing the allergic AEs of it and minimizing the immediate toxicity is paramount for importance so that you can proceed with the subsequent escalation of the dosing in this case. Also, compliance with the rate of discontinuation will decrease with the management of those AEs, which the majority of them are more for the engager part that’s inducing it, including the rash and perineum care, et cetera. Compliance from the patients can transmit an improvement in the PFS and OS of the patient.

Leventakos: Any practical tips for implementing these proactive strategies into the clinical practice?

Dimou: Get a thoracic pharmacist.

Leventakos: That brings up the next thing, which was what are the challenges that might arise with integrating proactive management strategies, and what tools and resources [might you use]? You both mentioned that we are blessed to have a thoracic oncology pharmacist, who has been doing the COCOON and the SKIPPirr [regimens] before they were even accepted.

It comes to something else that nobody openly talks about, which is time toxicity, not only for the patient but also for the care team because it's different. Our resources are limited, and having to deal with AEs for 3 hours is a different burden than having to deal with AEs for 10 minutes. Changing the education of the whole care team is something new because our brains have been studying for so many years, and we know how to get things, but still, it takes time. It doesn’t only have to work, but it also has to be easy. This amount of easiness is something that we try to capture in different ways in quality of life. We are blessed to have an amazing supportive team for us when using amivantamab. I don’t remember the last time that I had to deal with an IRR.

How much did this data change your opinion about the first-line [amivantamab]? The main data that I would like to bring up is that reactions are manageable; probably for dermatologic toxicity, there will be something better, and for subcutaneous, something is coming. How do you feel about changing your first-line or your second-line [therapy] right now? What would make you change your second-line?

Shanshal: The main question is, what would be the sequence here? To me, I still prefer the chemotherapy plus osimertinib [Tagrisso]. Having said that, the data for subcutaneous amivantamab is promising. If you look at the OS benefit and the HR, and that goes down to the mechanism function of this drug, there is also some natural killer activation. I’m wondering if this has to do with the lymphatic uptake. I’m looking closely at the subcutaneous data as a very convenient option for those patients as well. Until then, I still prefer chemotherapy plus osimertinib.

Parikh: It makes sense to prefer subcutaneous over IV. One question to ask is, would you still consider single-agent osimertinib in any of these patients in the frontline? There are prospective trials ongoing. I’d be very curious to see if those patients who have positive ctDNA at the third cycle and get 2 or 4 cycles of carboplatin plus pemetrexed at that time would have similar outcomes then. Would they have an improvement in those outcomes? That way, are we able to spare some patients from either amivantamab plus lazertinib or chemotherapy plus osimertinib and still have a role just for single-agent osimertinib in those patients.

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. Leighl NB, Akamatsu H, Lim SM, et al. Subcutaneous amivantamab vs intravenous amivantamab, both in combination with lazertinib, in refractory EGFR-mutated, advanced non-small cell lung cancer (NSCLC): Primary results, including overall survival (OS), from the global, phase 3, randomized controlled PALOMA-3 trial. J Clin Oncol. 2024;42(17):LBA8505. doi:10.1200/JCO.2024.42.17_suppl.LBA8505
3. Cho BC, Girard N, Sauder MB, et al. P3.12D.04 Enhanced vs standard dermatologic management with amivantamab-lazertinib in advanced NSCLC: phase 2 COCOON study. J Thorac Oncol. 2024. 1200-1400. doi.10.1016/j.jtho.2024.09.626