Study 309/KEYNOTE-775 Trial Design

Brad Monk, MD, FACOG, FACS: I was so excited when all of you agreed to participate. Vicky, I was excited to hear you because you have been very busy with this trial. This trial has 2 names; many people call it KEYNOTE-775. It is a collaborative study between 2 sponsors. The other name, the number is 309. You can either call it 309 or 775. You should probably use both names. This is a randomized phase 3 trial in second-line endometrial cancer. It was the physicians’ choice of chemotherapy, and we are going to hear what those medications were, versus pembrolizumab and lenvatinib in all-comers. Certainly, the accelerated approval came in September of 2020 in the non–MSI-high [non–microsatellite instability-high] subgroup.

In the US, it’s been, “Oh, all second-line patients basically need pembrolizumab,” since September of last year. If you are a patient with MSI-high tumors, you get pembrolizumab; if you’re non–MSI-high, you get pembrolizumab and lenvatinib, but we needed a higher level of evidence. Vicky, congratulations. I know this has been a substantial portion of your career, and you are close to the finish line. The finish line will be publication in The New England Journal of Medicine, which is virtually assured. The real finish line is bringing this to the clinic, and you are very close. I am so excited for you to take quite a bit of time. Take your time and tell us about this trial. Add some flavor. It was just presented at the Society of Gynecologic Oncology annual meeting.

Vicky Makker, MD: Thank you, Brad. I will try to add some Indian masala to the presentation. I have to say, though, before I begin, that this really has been a labor of love. It has been a beautiful collaboration, not only among our United States colleagues but also our international colleagues; we have all become great friends. It has been a wonderful experience, so I will humbly present this on behalf of all my colleagues, but this has been a labor of love on all our parts.

With that, essentially, as we have all talked about already, there continues to be a huge unmet need for the development of effective therapies for advanced recurrent endometrial cancers, specifically for those that are microsatellite stable [MSS] or mismatch repair [MMR] proficient because they comprise the majority of the recurrent disease space. As we have also talked about, checkpoint inhibitors have shown strong efficacy in the treatment of MSI-high or mismatch repair-deficient endometrial cancers. KEYNOTE-146 was the phase 2 trial that set the stage for and established the efficacy of lenvatinib, which is an oral TKI [tyrosine kinase inhibitor], in combination with pembrolizumab in advanced or recurrent endometrial cancers.

Again, this was a phase 3 study to compare the efficacy of lenvatinib and pembrolizumab versus a treatment of physicians’ choice [TPC]; there were 2 options, and we had a lot of input from all our international colleagues about what would be the best comparators. Essentially, those were doxorubicin or weekly paclitaxel. Essentially, key eligibility criteria for this study were that patients had to have advanced metastatic or recurrent endometrial cancers; they had to have measurable disease. The radiology assessments were done by blinded independent review for this study. Patients had to have 1 but were allowed 2 prior lines of platinum-based therapy. However, 1 had to be administered in the neoadjuvant or adjuvant setting if they had 2 priors. There was no restriction on prior hormones, and patients were stratified by MMR status.

Within the MMR-proficient group, they were further stratified by ECOG performance status, region, and prior pelvic radiation therapy history. Eligible patients were randomized 1:1 to lenvatinib 20 mg orally once daily, plus 200 mg of pembrolizumab IV [intravenously] every 3 weeks versus TPC, where again the choices were doxorubicin, which was given weekly at 60 mg per meter squared, or weekly Taxol [paclitaxel] at 80 mg per meter squared—3 weeks on, 1 week off. Pembrolizumab could be administered for a maximum of 35 doses, which is consistent with its labeling; the lenvatinib could continue beyond that point as long as, of course, the patient was clinically benefiting.

The cumulative maximum dose of doxorubicin was 500 mg per meter squared. There were dual primary end points of progression-free survival by blinded independent central review and overall survival. Secondary end points included objective response rate, and quality of life analysis results, which we are very much looking forward to hearing more about at ASCO [the American Society of Clinical Oncology annual meeting] this year, as well as safety. A key exploratory end point was the duration of response.

Transcript Edited for Clarity