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AACR 2021 | KEYNOTE-555: pembrolizumab bioavailability after subcutaneous administration in melanoma

Conrad R. Jacobs, MD, of GVI Oncology in Cape Town, South Africa and Dr Bolaji Akala, who is Senior Clinical Director of Early Oncology Clinical Development at Merck Research Labs MSD, share an update on the KEYNOTE-555 trial (NCT03665597) of pembrolizumab bioavailability after subcutaneous administration in patients with metastatic melanoma. Dr Akala reports that pembrolizumab received FDA approval at a dose of 400 mg every six weeks (Q6W) on the basis of results from cohort B of the KEYNOTE-555 trial. Cohort A, which enrolled 36 patients is focused on evaluating bioavailability. This interview took place at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021.

Transcript (edited for clarity)

Conrad R. Jacobs:
The trial was done, KEYNOTE-555. It was an analysis in metastatic melanoma, and the idea behind the trial was to check bioavailability of subcutaneous administration of pembrolizumab. Now, the background to this is that we know that pembrolizumab is a potent humanized monoclonal antibody against the PD1 receptor and it’s approved in multiple tumor lines, including melanoma...

Conrad R. Jacobs:
The trial was done, KEYNOTE-555. It was an analysis in metastatic melanoma, and the idea behind the trial was to check bioavailability of subcutaneous administration of pembrolizumab. Now, the background to this is that we know that pembrolizumab is a potent humanized monoclonal antibody against the PD1 receptor and it’s approved in multiple tumor lines, including melanoma. We know that pembrolizumab, up until this point in time, has been given intravenously and the dose that we have been using and that’s been registered has been 200 milligrams every 3 weeks. There’s also other fun pharmacokinetic done in the cohort B of KEYNOTE-555, where it was evaluated to see that a dose of 400 milligrams could be given every 6 weeks, and I think recently, Bolaji can help me there, it’s been approved by FDA to give at that dose.

Bolaji Akala:
So Q 6 weeks, KEYNOTE-555 had two cohorts. The one we’re presenting today is cohort A, but we also had a cohort B that was 400 milligrams Q 6 weeks, and we’ve had approval in the FDA, in Japan, in the EU, in China, multiple markets, based on the results of that trial, which Dr. Jacobs was also one of the significant players, principal investigators, in that portion of the study

Conrad R. Jacobs:
That was the KEYNOTE-555 cohort B, so the 400 milligrams is the alternate dose. We know that there are other monoclonal antibodies that are given subcutaneously and have been working quite well and we’re looking at Herceptin as one of them. I think the idea behind the trial was to see if the bioavailability of pembrolizumab, given subcutaneously, would be acceptable. There are various reasons for it. It’s easier to administer, it can be administered off-site, it reduces the time of preparation, and it is just more convenient to the patient.

Conrad R. Jacobs:
It’s an open-label phase 1 study, and the cohort A was to evaluate the bioavailability of the administration of pembrolizumab. Then, I’m going to just highlight the objectives of the trial was to characterize the PK profile of the subcutaneous pembrolizumab, particularly the absorption phase, to estimate the relative bioavailability of subcutaneous pembrolizumab in the two different formulations that was given. The one was 130 milligrams per milliliter, and the other 165 milligrams per milliliter, so they were two volumes of administration. And then the secondary objectives were to evaluate the development and circulating anti-pembrolizumab antibodies after subcutaneous administration of the pembrolizumab, and also to evaluate the safety and tolerability, including site reaction and obviously any other reaction and safety that happens with it.

Conrad R. Jacobs:
There were 36 patients in the trial, 6 in each arm. The median age group of the patients were 60, mostly male, all of them were Caucasian or white. 10 patients were done in Australia and 26 patients in South Africa. Mostly ECOG 0, a good performance status mostly, and all clinical staging with a stage 4, except for one patient. So 35 patients were stage 4. No prior therapy in 30 of the patients, and prior adjuvant therapy in 5.

Conrad R. Jacobs:
If we look at the outcome of this and we analyze that, the PK values and things were very well-documented on our poster. First we mention that the pembrolizumab CRM data was collected and the absorption phase of the subcutan was characterized by a first-order absorption and the bioavailability parameters. Distribution and elimination phase were described by a two-compartment model. The inclusion of covariate effects for the strength of the subcutaneous formulation or use of distinct absorption models for each SubQ patient were not statistically significant, indicating no meaningful difference in the bioavailability of the two formulations that were used. The estimated bioavailability of the absorption was 66%, with a confidence interval of 58% to 74%.

Conrad R. Jacobs:
Very few adverse events were documented, of none greater than stage 1 or 2, and most of the symptoms that were documented or measured was a pain, itching, swelling, or erythema. We only found that there was erythema in 2 or 3 patients evaluated.

Conrad R. Jacobs:
As far as the conclusion is concerned then, is that the analysis showed that subcutaneous administration of pembro, that an estimated bioavailability of 66%, which was consistent with the bioavailability reported for other monoclonal antibodies administered subcutaneously. The two tested subcutaneous formulation strengths had similar absorption PKs. The subcutaneous administration was well-tolerated with no adverse events, so the subcutaneous dose can achieve the same effect as the 200 milligrams intravenously given every 3 weeks. That is the trial.

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Disclosures

Bolaji O. Akala, MD, PhD, is a Merck employee and a Merck stock holder.

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