Low-Dose Chemotherapy With Immunotherapy Shows Efficacy in UC

Rhonda L. Bitting, MD

While single-agent checkpoint inhibitors can be an effective treatment option for some platinum-refractory urothelial carcinoma (UC) patients, additional therapies are needed, according to Rhonda L. Bitting, MD, and other experts. Low doses of chemotherapy may help to increase the efficacy of immunotherapy.

A phase 2 single-arm study (NCT02581982) is testing this hypothesis explored the combination of low-dose paclitaxel and pembrolizumab (Keytruda) in up to 29 patients with platinum-refractory UC. The primary end point of the study is overall response rate, and the secondary end points include progression-free survival (PFS) and the incidence of adverse events (AEs).

An analysis of the study published in the Journal of Clinical Oncology showed that all patients received pembrolizumab over 30 minutes on day 1 and paclitaxel over 60 minutes on day 1 and 8. Treatment repeated every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity. The ORR observed in these patients was 33%, and the disease control rate was 72%. Treatment with the low-dose chemotherapy and immunotherapy combination also led to a 6-month PFS rate of 46.8% (95% CI, 27.2%-64.2%), and a median OS of 11.7 months (95% CI, 8.7 months to not reached).

In an interview with Targeted Oncology™, Bitting, an associate professor of Medicine at the Duke Cancer Institute, discussed the efficacy results and key takeaways of a study investigating low-dose paclitaxel plus pembrolizumab in patients with platinum-refractory UC. 

TARGETED ONCOLOGY™: What are some key unmet needs for patients with platinum-refractory urothelial carcinoma?

Bitting: When urothelial carcinoma is, it is a life-threatening disease, and we currently have a couple of options to treat folks who present after progression on platinum chemotherapy. However, all of those options come with potential toxicities, and there's some overlap. So, for example, we have several different immunotherapy options that you don't give sequentially, you have to choose one or the other in that setting. We also have targeted therapy that is only appropriate for patients with very specific gene mutations. So, we have a need to reach a broader audience, a bigger group of patients, and potentially allow them to live longer and better. 

Can you provide some background on your study of low-dose paclitaxel with pembrolizumab? What was the rationale for using these 2 agents together?

Pembrolizumab is approved in platinum-refractory metastatic urothelial carcinoma. However, in a very similar population to what was studied here, only about 20% of those patients responded. So, we were trying to figure out how to make this drug work better for more patients. Based on some preclinical studies that showed that giving low-dose chemotherapy, so not enough to completely wipe out the bone marrow, but chemotherapy at a lower dose, may modulate the immune system and modulate the body's inflammatory response to allow the immune therapy to work better.

What did you look at prospectively? What patient characteristics did you look for this study?

This study was specifically for patients with metastatic urothelial carcinoma, who had progressed within a year of receiving prior platinum therapy. That could have been carboplatin or cisplatin. They had to have an ECOG performance status of 0 or 1 and overall organ function that was acceptable in terms of blood counts, kidney function, liver function. Patients weren't eligible to be part of this study if they had a significant neuropathy underlying or if they had previously been treated with an anti PD-1 or PD-L1 therapy, or a prior taxane therapy.

What were the results that you presented for ASCO GU?

So, the overall goal of the study was to evaluate the ORR. What we found was that when you evaluated by intention to treat, 9 of the 27 patients had a response. And of those with response, 3 of 9 ended up being a complete response.

What are your key takeaways from these results?

We found that combining low-dose paclitaxel with pembrolizumab resulted in better response rates than treatment with pembrolizumab alone. We also found that the treatment was relatively well tolerated. So, although there were some adverse events, there was no unanticipated safety signals that emerge from this study.

There were a couple of patients who had immune mediated adverse events. As has been repeated reported previously, those patients actually went on to have a good response to treatment. Otherwise, the common adverse events were anemia, lymphopenia, hyperglycemia, and fatigue.

Are there any next steps with this research?

We're specifically looking at the PD-L1 status of the tumors, as wel as looking at tumor mutational burden. Importantly, we're also looking at the change in the number and proportion of immune cell populations, including effector, and regulatory T cells, and myeloid derived suppressor cells. We're also looking at immune regulatory micro RNAs in both the blood and urine and trying to see if any of these combinations of biomarkers may help us to better figure out who responds to this combination and who does not.

_REFERENCE:

_{Bitting R, Vile D, Tooze D, et al. Single-arm phase II study of low-dose paclitaxel and pembrolizumab in platinum-refractory metastatic urothelial carcinoma (UC). J Clin Oncol. 2021; 39(6): 433-433. doi: 10.1200/JCO.2021.39.6_suppl.433}