Petros Grivas, MD, from the University of Washington Fred Hutchinson Cancer Research Center, shares results from the phase 2 TROPHY-U-01 trial evaluating the use of sacituzumab govitecan in combination with pembrolizumab for patients with metastatic urothelial cancer who progressed after platinum-based regimens, including encouraging response rates and a look to the future.

Transcript:

I'm Dr. Petros Grivas, I'm a medical oncologist at the University of Washington Fred Hutchinson Cancer Center. I'm serving here as a clinical director for GU Group and I'm very, very excited to report to you some important data that were presented at the ASCO GU 2022 a few months ago. Looking at the combination of pembrolizumab, anti-PD-1, and sacituzumab govitecan, it's called SG, which is an antibody drug conjugate against Trop2, linked conjugated with metabolite irinotecan called SN-38. This drug has an accelerated approval in metastatic urothelial cancer after treatment with a platinum based chemotherapy and checkpoint inhibitor, and there is an ongoing Phase III trial to confirm the value, in terms of overall survival in the future.

In this study, we evaluated this combination, and I want for context, just to remind the audience, that patients with metastatic urothelial cancer have been treated initially upfront with platinum based chemotherapy, ideally cisplatin based, for example, gem/cis. Or, if they're not fit for cisplatin, with carboplatin/gemcitabine.

In either way, switch maintenance avelumab is a standard of care for patients with CR, PR, or stable disease to platinum-based chemotherapy, because overall, end progression for survival benefit, significant benefit, based on the results of the JAVELIN Bladder 100 trial, that were presented about two years ago at ASCO 2020 meeting.

For patients who are not fit for any platinum, cisplatin and carboplatin not eligible patients, about 10% in my practice, I use checkpoint inhibitor by itself, pembro or atezo, based on results of Phase II and Phase III trials, that saw activity, in terms of durable responses in proportion of patients in the setting. However, in the US, you do not need to test PD-L1 to use checkpoint inhibitor for platinum ineligible patients. In Europe, you need. There's a difference there. But because of that, I do not check PD-L1 testing in front-line setting. I use platinum based chemo, cis ideally, or gem/carbo, followed by avelumab, in either case, if there's no progression. And for those who are not fit for avelumab, I give checkpoint inhibitor.

There's also a role for antibody drug conjugates, enfortumab vedotin, sacituzumab govitecan as we talked, and erdafitinib, the latter, only for patients with an activated mutation or fusion in FGFR2 or FGFR3 for platinum refractory disease, in selected patients based on accelerated approval with erdafitinib in a single arm Phase II trial.

Overall, the landscape has evolved significantly. We're very excited about it. But of course, we're looking for further agents and combinations as well as biomarkers to further improve the field. And especially, for patients who are not eligible for any platinum, or patients who are platinum refractory upfront, primary refractory to platinum, there is definitely an admit need. And we looked at the combination of sacituzumab govitecan plus pembrolizumab, especially in those platinum refractory patients.

That's the point here, the response rate with checkpoint inhibitor alone, is about 20% with pembro second-line, based on the KEYNOTE-045 trial. The question is, can we improve upon that with combinations? For example, in ADC, sacituzumab govitecan plus pembrolizumab.

That is the structure, as I mentioned before, anti-Trop2 antibody and a linker with hydrolysable and the high drug-to-antibody ratio connects the links that antibody to a toxin, which is called SN-38, is a very active metabolite for irinotecan, a topoisomerase I inhibitor.

We know that antibody drug conjugates could potentially induce immunogenic cell death, can release new antigens, and this can set the stage for synergism and additive effects with immune checkpoint inhibitor. And we hypothesize that, we can achieve that with sacituzumab govitecan plus pembrolizumab.

There's also some interest in preclinical data, looking at the upregulation of MHC and the androgen presentation process, and potential for increasing of PD-L1 expression and potential synergism between the two molecules, again, in a preclinical context. So we have to do the clinical test to see that's the case.

Our focus will be cohort three, up to 61 patients with a combination of pembro plus SG, single arm, non-randomized trial, objective response rate was the primary endpoint. And this was based on investigator assessment for the cohort three.

The data so far, suggests that the dose of sacituzumab can be 10 milligrams per kilogram. That was a single agent data that we published in JCO for cohort one, that led to the accelerated approval of this agent SG, in patients with platinum chemotherapy and checkpoint inhibitor in the past that had progression. And we hypothesize here, that if we see a target response rate of at least 20% or higher, that would require further investigation. We want to see at least 13 responses to, so we can say that the hypothesis of a response rate below or up to 20% would be rejected with one sided alpha of 0.05. We saw an objective response rate of 34%, 14 patients, that was met the primary endpoint. We want 13 or higher response in 41 patients. We saw one complete response in 13 partial responses. And about four additional patients had stable disease, at least for six months.

The overall clinical benefit rate, if you add CRP and a stable disease at any time, was 61%. And about two thirds of the patients have some degree of reduction in the tumor size on scans. Definitely, there's activity from this combination and the median follow up was about six months. The median time to response was the first scan, about two months. Median duration of response was not reached. And the median PFS was about 5.5 months. Median OS not reached. Of course, this is single arm not randomized study, so median PFS and OS has to be interpreted with a grain of salt.

To conclude, the combination of SG plus pembro in the second-line platinum refractory setting in immunotherapy naive population, had encouraging efficacy with a response rate of 34%, 38% available patients, meeting the primary endpoint. And clinical benefit rate exceeded 60%. Median PFS, single arm study, not low, minus 5.5 months. At the median follow up approaching six months, median duration of response in OS were not reached.

And this combination had a manageable toxicity profile, with no new safety signal, and no increase in systemic surgery requiring in mutilated adverse events, is what you expect for pembro and SG alone. You saw this effect in the toxicity profile.

The data, in my humble opinion, support further evaluation of the combination. The questions were, where do you do next? Do you do a Phase III trial in second-line? Do you go first-line? Do you evaluate triple therapy with further combinations? Remains to be seen. And additional follow up and biomarker work is ongoing.

I want to also focus your attention, there are additional cohorts, cohort four and five, and cohort two, that we're going to report in the near future. And of course, there is a Phase III trial called TROPiCS-04. Phase III trial, trying to confirm overall survival benefit of SG versus taxanes and vinflunine. We don't have data yet, the trial is ongoing, and hopefully will report in the future. If you have it available, think about TROPiCS-04, sacit versus taxane in the US, or versus vinflunine in Europe, Phase III trial after platinum based chemotherapy, after immunotherapy is ongoing and occurring.

And thank you so much for your attention.

Source:

Grivas P, Pouessel D, Park CH, et al. TROPHY-U-01 Cohort 3: Sacituzumab govitecan (SG) in combination with pembrolizumab (Pembro) in patients (pts) with metastatic urothelial cancer (mUC) who progressed after platinum (PLT)-based regimens. Presented at: American Society of Clinical Oncology; June 3-7, 2022. Chicago, IL, and virtual. Abstract 434.