Immune Checkpoint Inhibitors Following Platinum Chemotherapy Regimens in Urothelial Carcinoma

Benjamin Miron, MD, Fox Chase Cancer Center, Temple University Health System, Philadelphia, PA, shares insights from a study looking at the impact of a first-line platinum chemotherapy agent (cisplatin vs carboplatin) followed by an immune checkpoint inhibitor monotherapy in the second-line treatment setting for patients with metastatic or locally advanced urothelial carcinoma.

Results from the study did not support any specific synergy between a platinum chemotherapy regimen and an immune checkpoint inhibitor. However, there was evidence to strongly support cisplatin as the preferred first-line platinum agent in this population.

Transcript:

Hi, I'm Benjamin Miron. I'm a medical oncology fellow at Fox Chase Cancer Center. I'm excited to speak with you today to present a study, on the behalf of my co-authors, that's titled "Influence of First-line Chemotherapy Regimen on Survival Outcomes of Patients with Advanced Urothelial Carcinoma Who Received Second-line Immune Checkpoint Inhibitors.” And the idea for this study was really sparked by some questions coming from the clinic, as the field of bladder cancer has evolved significantly with new therapies available to us over the last 5 years, specifically PD-1 /PL-1 immune checkpoint inhibitors, which have really become a part of the treatment paradigm at some point for most patients with advanced disease. That led to a lot of questions about how to best sequence, or plan, our treatments.

Despite some of those advances I just mentioned, the first-line standard of care at this point remains platinum-based chemotherapy for patients who can get it, usually with either cisplatin- or carboplatin-containing regimens. We know historically that cisplatin is more efficacious than carboplatin with higher response rates and improved survival, but that comes at the price of toxicity.

We had a question that came up, especially given that fact that maybe there might be a reason to see if there was a specific interaction between cisplatin and carboplatin with immunotherapy given in the second line, with the understanding that there are no differences in the first line. We wanted to see if that translated to any differences in the second line. Some of the reasoning for that question was also based on the fact that chemotherapy control arms from moderate clinical trials of bladder cancer suggest that carboplatin was performing maybe a little bit better than we had expected or seen historically.

The hypothesis we came in with was that maybe some of the patients who got subsequent therapy with immune checkpoint inhibitors that might have closed the gap in efficacy between these 2 agents. There's also some ongoing discussion and questions about the immunogenicity of certain chemotherapy agents, specifically cisplatin and some work being done by other groups looking at that on a basic science level as well.

The question is pretty simple: How does first-line cisplatin versus carboplatin influence survival on second- line immune checkpoint inhibitors? We tried to answer this question using real world data set powered by Flatiron Health's database. We recently published a full manuscript with some updates to the initial data that we presented at as a poster at ASCO in 2021. The database has a large cohort of patients who got first-line chemotherapy with the agents that we were interested in, so about 2000 patients. And that was split nearly in half down the middle for both regimens equally. In this group of patients that got first-line chemotherapy about half of them got single agent immune checkpoint inhibitors as a second-line therapy. And that was really the population that we were looking at for the primary end point, which was overall survival from the start of second-line therapy. For the purposes of this analysis, we excluded maintenance immune checkpoint inhibitors—they had just been approved and they weren't really well represented in the database.

To get to the top line result, essentially what we saw was that unadjusted overall survival starting from second line of therapy with immune checkpoint inhibitors was statistically longer for patients who got gemcitabine-cisplatin compared to gemcitabine-carboplatin followed by immune checkpoint inhibitors. But the difference, while statistically significant, wasn't clinically meaningful, it was only about half a month or two weeks.

This was a retrospective study and because of that, we wanted to account for covariance that might confound these results, because we know that patients who get gemcitabine-cisplatin are generally a little bit more fit. We saw that, based on the demographics of these patients. When we adjusted for covariance, there was no difference at all in survival on immune checkpoint inhibitors in the second line, the hazard ratio was 0.94. We thought that was an important finding.

I think another important caveat to this data, when you're thinking about these results, it's important to remember that the primary analysis that I just described only includes patients who needed some second-line treatment. It might leave out patients who did very well with chemotherapy in the first line. To look at those patients, we did some exploratory work in the form of a best responders analysis—patients who are alive, didn't progress, and didn't have a reported second line of treatment within the database. Looking at those patients, we did see that there were more of them who had gotten cisplatin in both 1 and 2 years. That first treatment with cisplatin definitely had a larger proportion of patients who are doing better at 1 and 2 years, based on these results and they may have not needed a second treatment. That's important to keep in mind.

Lastly, we also did a time-dependent covariate analysis, which was driven by our amazing bioinformatician, Dr Beth Handorf [PhD, Fox Chase Cancer Center]. In simple terms, essentially it looks at the influence of various factors, notably which chemotherapy patients got overall survival over time. What that means is during the time that they're getting chemotherapy, how did different regimens influence their survival, but also at other points in their treatment, how did that chemotherapy regimen influence their survival? The main takeaway was that while patients were getting chemotherapy, there's a clear advantage to cisplatin over carboplatin, but once they were on second-line immunotherapy, there was no impact of those chemotherapy regimens on survival during that time forward.

I think these were some interesting results and essentially led to the conclusion that survival on immune checkpoint inhibitors wasn't significantly impacted by the type of prior platinum chemotherapy agent based on these results. Real-world data that I just talked to you about doesn't support a specific immunogenicity or a synergy of cisplatin as compared to carboplatin with immune checkpoint inhibitors in promoting more immunogenic environment. Again, this is with the caveats that I've mentioned.

Also, it's very important to remember that in this study and from what we knew before, cisplatin is associated with much greater efficacy and durable benefit in the first line. I think that this study doesn't necessarily change your decision-making in the first line. If a patient can tolerate cisplatin, that's the right choice. But once patients have gotten to a second line, it can be nice to be able to encourage them that they'll have the same chance at a good response whether they had cisplatin or a carboplatin previously. That was kind of the main claim of our study.

Source:

Miron B, Handorf E, Zarrabi K, et al. Influence of first-line chemotherapy regimen on survival outcomes of patients with advanced urothelial carcinoma who received second-line immune checkpoint inhibitors. Urol Oncol. 2022;40(10)454.e9-454.e16. doi:10.1016/j.urolonc.2022.05.028