Expert: PALOMA-3 Trial Results, Benefits of Subcutaneous Amivantamab for Lung Cancer Treatment

In an interview with Pharmacy Times, Natasha B. Leighl, BSc, MMSc, MD, Medical Oncologist at the Princess Margaret Cancer Centre in Toronto, Canada discussed the PALOMA-3 trial results, shared at the American Society of Clinical Oncology 2024 Conference. Leighl noted that the trial compared subcutaneous and intravenous administration of amivantamab for lung cancer. She discussed that subcutaneous administration significantly reduced infusion reactions and improved overall survival. It also decreased administration time from 5 hours to 5 minutes. Leighl emphasized these results suggest subcutaneous amivantamab could replace intravenous administration to improve patient outcomes and experience of care.

Just to start, what is the regimen assessed in the PALOMA-3 trial and what did the efficacy results show regarding the benefits of this regimen compared to current standard of care?

Thanks. So currently amivantamab is approved for use in patients with specific types of genomic driven lung cancer, EGFR positive lung cancer, and the approved formulation is intravenous. One of the limitations of course, is that it can take longer, the first infusion often will take more than 4 hours. We need split dosing in day 1, cycle 1 and then afterwards, it's not split dosing, and subsequent infusions take 2 hours. So the time of administration, of course, is a challenge for patients and for providers.

The other thing that we saw with amivantamab was that there was an infusion related reaction rate. Usually in the first hour of cycle 1 day 1. It didn't recur, but of course, that can really throw a wrench into the works and the infusion related reaction rate was 67% with the IV formulation, so the subcutaneous amivantamab program was developed aimed at really decreasing that administration time. And in the PALOMA dose finding study, what we found was that, as we established the recommended phase 2 doses for the different intervals we explored, patients had significantly fewer IRRs. So in PALOMA 3, we compared subcutaneous and amivantamab to intravenous amivantamab, both with lazertinib— a third generation EGFR kinase inhibitor in patients with previously treated EGFR mutant lung cancer, who had failed targeted therapy osimertinib, and platinum chemotherapy.

So, what we found was that first of all, the pharmacokinetics were non inferior. We look at trough levels at cycle 2 day 1 also, at cycle 4 day 1 and the geometric mean ratios were 1.15 initially, and then 1.43 later on, at the steady state what you'd expect with subcutaneous administration. And also cycle 2-day 1 air under the curve. Also, the area under the curve at cycle 2, you know, the GMR was more than 1 and so clearly not inferior.

We also looked at efficacy outcomes because that's so important, you know, when you're going to switch this over in patients with advanced cancer. We found that the response rate was non inferior 30 and 33% in the subcutaneous and intravenous arms. To reach the response was longer, which was interesting 11.2 months was subcutaneous, compared to 8.4 months with intravenous progression free survival trended to being longer with the second tennis version. And the hazard ratio for that .84 but it wasn't significant. But what was really surprising to us and what we were not expecting, was that overall survival significantly favor the subcutaneous arm, the hazard was 0.62, which is of course a big deal in patients with advanced lung cancer. And the p value was statistically significant. That was a pre-planned exploratory analysis, the p value was 0.02. For the endpoints that we originally set out to look at things like IR Rs and treatment duration, we found that the use of subcutaneous amivantamab significantly decreased the rate of IRRs more than fivefold at 13%, compared to 66% with IV. No patients discontinued for IRRs or hospitalized in the subcutaneous arm, that it was uncommon, but did happen. There were a few events in the IVR.

Key Takeaways

Subcutaneous amivantamab significantly reduced infusion-related reactions compared to intravenous administration.
It improved overall survival outcomes for patients with advanced lung cancer.
Administration time was reduced from 5 hours to just 5 minutes, improving convenience for both patients and providers.

When it came to treatment administration, we were able to get that treatment in in less than five minutes and median of 4.8 minutes, compared to five hours on day one of IBM event map and then of course, you have to come back for split doses or cycle two, and then two hours on subsequent cycles. So, it really has made a transformative difference to the patient and provider experience. In 5% of patients said that they found the subcutaneous administration convenient or very convenient, using the modified treatment administration satisfaction questionnaire, and that was significantly more than that then in the intravenous arm. The other thing that we've noticed is that when we combine amivantamab with lazertinib, we didn't really notice this in our initial studies, but we did see it in the randomized MARIPOSA study, a first line treatment, the rate of DVT and pulmonary embolism was quite high unexpectedly at 37%. So, in PALOMA-3, this was the first study where we actually use prophylactic anticoagulation. We anticoagulated patients for 4 months during their initial treatment. And what we found was that significantly decreased the rate of VTE. So, from 21% in the small number of patients, only about 20% of patients refused or didn't go on prophylaxis. Their rate of ZTE was 21%. And if you did go on prophylaxis, it was 10%. So, a clear reduction. Everything we found was that in the subcutaneous arm whether you receive anticoagulation or you didn't, the rate of VT was lower. So just to sum up employment three, we showed that subcutaneous amivantamab plus lazertinib was pharmacokinetically, non-inferior, had non inferior response trended to better outcomes had significantly improved survival for reasons we don't yet understand. But we're looking into at vastly shorter administration time, 5 minutes compared to 5 hours plus split dosing, and had much greater patient convenience, as well as better safety with lower rates of IRR, significantly lower rates, virus, and less, VTE.

What are the administration benefits of subcutaneous amivantamab in terms of the clinic wait times? And how can this impact oncology practice if they are implemented?

Today, we have more and more patients getting more and more therapies, more of these are complex drugs, bispecific, CAR T so many things that require so much more chair time, and so much more nursing and pharmacy time and physician time to administer. And of course, patients are doing so well, they're on these treatments longer. So there really are starting to be queues around the world for all of these different treatments. And so, with intravenous amivantamab, patients on the first day have to come for day 1 and day 2, we split the dosing. The first day is 5 hours, the second day is anywhere from 2 to 4 hours and then subsequent visits are 2 hours. If your patient has a reaction, of course, like with daratumumab or rituximab, you know, that just puts everything on hold. We've got to manage the reaction. Patients are worried, you know, it takes up time from the nursing team and takes time away from other treatments that we could be giving. And so, what's great about subcutaneous me that's that was we really ratcheted down the IRR rate from 66% to 13%, less severe, and you can get treatment in five minutes. So, we use a 21 gauge needle, you can get the dose that we used in PALOMA-3, you can get into 10 MLs, it is formulated with hyaluronidase. We will administer that over 5 minutes in one of the abdominal quadrants, and then we just rotate. The patients and the team that's administering this, it goes really well they really tolerate it well, much better than our initial expectations. I think when we all have, we investigators of lung cancer, that we were going to get the subcutaneously without or was going to be a disaster. But it was amazing, you know how well it worked. Patients loved it, we do have about 9% of local reactions, but it really just tends to be redness, which settles down before the patient goes home. In the study, we did observe patients for up to four hours. But I don't think that patients really need that we did not really see a marked incidence of delayed reactions was were very uncommon. Of course, you need to teach your patient what to call for. But you know, you can probably send patients home very soon after this. So, when you think about 5 hours, 2 days, and suddenly we're down to 5 minutes. I mean, that's a huge impact on our ability to deliver this drug well and safely.

Yes, definitely. That's great to hear. Moving forward, do you see potential for moving this regimen to an at home access for patients in the future?

Great question. The goal of the subcutaneous program is to establish this to really replace all of the intravenous amivantamab indications. I think right now, this needs to be given in the clinic with appropriately trained staff with observation. There is a low rate of hours but it does exist and so I think today with the results of the PALOMA-3, we would still recommend that this be given in a supervised setting. We will see what the future holds. You know, there's a lot of excitement for home delivery of medicines. I think what is great though is that smaller clinics and clinics with less staff could much more easily administer subcutaneous amivantamab, whereas it probably takes quite a big unit to administer IBM amivantamab like IV rituximab or daratumumab. You really need more staff around in the case of reaction with the the higher likelihood of reaction so, I think that we are expanding the ability to get this closer to patients’ homes. We're not at home yet.

So, it is our plan at to submit for registration. It's our hope that the regulators around the world will recognize the value of this as investigators were very excited by this shift. Then the plan is to incorporate this into all of the me vast number of regimens. We have Q2 Weekly Q3 Weekly Q4 weekly dosing, a range of indications across types of cancers. And then of course, to build on different combinations from there. We also published some data on PALOMA-2 as a poster at ASCO where we showed some very nice test data, looking at response rates with different combinations. For example, within the MARIPOSA first line, EGFR mutant lung cancer setting, we showed that response rates were really similar when we use subcutaneous ami versus IV ami plus lazertinib in that first line setting. So, really great potential to change the way we do things across the map.