Pharmacy Focus
S2 Ep28: Pharmacy Focus: Oncology Edition- Benefits of Subcutaneous Amivantamab for Lung Cancer Treatment
(upbeat music) Hi, I'm Kennedy Fruggia with Pharmacy Times and you're listening to pharmacy focus oncology edition, where we break down the latest news in the oncology pharmacy space. (upbeat music) On this episode of pharmacy focus, we talked with Natasha Villal, a medical oncologist at the Princess Margaret Cancer Center, which is located in Toronto, Canada. She discussed the Paloma 3 trial results, which were shared at the American Society of Clinical Oncology 2024 conference. 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, Amy Vantimav has approved for use in patients with specific types of genomic-driven lung cancer, each of our positive lung cancer. And the approved formulation is intravenous. And one of the limitations, of course, is that it can take longer. The first infusion often will take more than four hours. We need split dosing in day one cycle one. And then afterwards, it's not split dosing. And subsequent infusions take two hours. So the time of administration, of course, is a challenge for patients and for providers. And the other thing that we saw with Amy Vantimav was that there was an infusion-related reaction rate. Usually in the first hour of cycle one day one, it didn't occur, 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 Amy Vantimav 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 two doses for the different intervals we explored, patients had significantly fewer IRRs. So in Paloma 3, we compared subcutaneous Amy Vantimav to intravenous Amy Vantimav both with a Zertanib, a third-generation EGFR kinase inhibitor, in patients with previously treated EGFR mutant, lung cancer, who had failed targeted therapy, osymoratinib, and rather platinum chemotherapy. So what we found was that first of all, the pharmacokinetics were non-inferior. We looked at trough levels at cycle two day one, also at cycle four day one, and the geometric mean ratios were 1.15 initially, and then 1.43 later on at the steady state, which you'd expect with subcutaneous administration, and also cycle two day one area into the curve. Also that the area under the curve at cycle two, the GMR was more than one, and so clearly non-inferior. We also looked at efficacy outcomes, because that's so important, you know, when you're gonna switch this over in patients with advanced cancer. And we found that the response rate was non-inferior, 30 and 33% in the subcutaneous and intravenous arms, duration of response was longer, which was interesting, 11.2 months was subcutaneous, compared to 8.4 months with intravenous, progression of free survival, trended to being longer with the subcutaneous version, and the hazard ratio for that was 0.84, but it wasn't significant, but what was really surprising to us, and what we were not expecting, was that overall survival significantly favored the subcutaneous arm, the hazard was 0.62, which is of course, big deal in patients with advanced lung cancer, and the P-value was statistically significant, and that was a pre-planned exploratory analysis, the P-value was 0.02. So for the endpoints that we originally set out to look at, to add things like IRRs and treatment duration, we found that the use of subcutaneous and event amount significantly decreased, the rate of IRRs more than five-fold at 13%, compared to 66% with IV, no patients discontinued for IRRs, or hospitalized in the subcutaneous arm. It was uncommon, but did happen, there were a few events in the IV arm. When it came to treatment administration, we were able to get that treatment in in less than five minutes, a median of 4.8 minutes, compared to five hours on day one of IV, IV, and event amount, and then of course you have to come back for split dose in episode two, and then two hours on subsequent cycles. So it really has made a transformative difference to the patient and provider experience. 85% 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 in the intravenous arm. The other thing that we've noticed is that when we combined an event map with LeZertinib, we didn't really notice this in our initial studies, but we did see it in the randomized Maraposa study, a first line treatment, the rate of DVT and pulmonary embolism was quite high unexpectedly at 37%. So in Paloma III, this was the first study where we actually use prophylactic anticoagulation. We anticoagulated patients for four months during their initial treatment, and what we found was that 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 VTE was 21%, and if you did go on prophylaxis, it was 10%. So a clear reduction. The other thing we found was that in the subcutaneous arm, whether you received anticoagulation or you didn't, the rate of VTE was lower. So just to sum up, in Paloma III, we showed that subcutaneous ami-vantimab plus LeZertinib 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 a vastly shorter administration time five minutes compared to five hours plus split dosing, and had much greater patient convenience, as well as better safety with lower rates of IRR, significantly lower rates of IRRs and less VTE. - But what are the administration benefits of subcutaneous ami-vantimab in terms of the clinic wait times, and how can this kind of impact oncology practices if they are implemented? - So today, we have more and more patients getting more and more therapies, more of these are complex drugs by specifics, 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 they really are starting to be cues around the world for all of these different treatments. And so with intravenous ami-vantimab, patients on the first day have to come for day one and day two, we split the dosing, the first day is five hours, the second day is anywhere from two to four hours, and then subsequent visits are two hours. If your patient is a reaction, of course, like with daratumumab or retuxumab, that just puts everything on hold, go to manage the reaction, patients are worried, 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 ami-vantimab is 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 and pull on the three, you can get into 10 mLs, it is co-formulated with high Lebronidase, we'll administer that over five minutes in one of the abdominal quadrants, and then we just rotate and 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 of our investigators and lung cancer heard that we were gonna get this subcutaneous, basically without all this is gonna be a disaster, but it was amazing 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, those were very uncommon. Of course, you need to teach your patient what to call for, but you can probably send patients home very soon after this. So when you think about five hours, two days, and suddenly we're down to five 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? - It's a great question. The goal of the subcutaneous program is to establish this, to really replace all of the intravenous and revamped map 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 IRRs, but it does exist. And so I think today, with the results of the Ploma3, we would still recommend that this be given in a supervised setting. We will see what the future holds. 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 and advanced map, whereas it probably takes quite a big unit to administer IBM advanced map, like IV retoxumab, or daratumumab, you really need more staff around in the case of reaction, or with 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 what are the next steps following these Ploma3 trial results? So it is our plan to submit for registration. It's our hope that the regulators around the world will recognize the value of this as investigators. We're very excited by this shift. Then the plan is to incorporate this into all of the ami-vantimab 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 Ploma2 as a poster in ASCO, where we showed some very nice data, looking at response traits with different combinations. So example in the Mariposa first line, each affirmative lung cancer setting, we showed that response rates were really similar when we used subcutaneous ami versus IV ami, plus the zirative and that first line setting. So we're really great potential to change the way we do things across the map. Pharmacy time, everything pharmacy, every day. (gentle music) (gentle music)