Immunotherapy Continues to Impress in GU Malignancies

Article

Andrea Apolo, MD, discusses the combination of cabozantinib plus nivolumab and ipilimumab, as well as the latest data on avelumab in urothelial carcinoma.

Andrea Apolo, MD

Andrea Apolo, MD

Andrea Apolo, MD

Single-agent immunotherapy continues to demonstrate durable responses in patients with urothelial carcinoma, and now, combination regimens are showing efficacy in both urothelial carcinoma and rarer genitourinary (GU) tumors.

In a phase I study, the combinations of cabozantinib (Cabometyx) plus nivolumab (Opdivo), as well as cabozantinib plus nivolumab and ipilimumab (Yervoy), are being investigated in patients with GU malignancies.1 Findings showed that, in the overall study population, the overall response rate (ORR) was 33%. Moreover, the ORRs with cabozantinib and nivolumab, and cabozantinib, nivolumab, and ipilimumab, were 38% and 22%, respectively.

In addition to patients with metastatic urothelial carcinoma, rare GU tumors such as penile cancer, testicular cancer, and adenocarcinoma of the bladder are responding to these therapies, as well.

Additionally, the anti—PD-L1 agent avelumab (Bavencio) showed durable responses in the phase Ib JAVELIN Solid Tumor study, an updated analysis of which was presented at the 2017 ESMO Congress.2

Andrea Apolo, MD, presented the results, which showed that the ORR in the 249 patients evaluated in the study was 17.3% (95% CI, 12.8%-22.5%), with a complete response rate of 4.4%. The disease control rate was 44.6% and the median overall survival was 8.2 months (95% CI, 6.3-10.8).

OncLive: Can you summarize the early findings with cabozantinib and nivolumab, with and without ipilimumab?

In an interview with OncLive at ESMO, Apolo, chief of the Bladder Cancer Section of the Genitourinary Malignancies Branch at the National Cancer Institute, discussed the combination of cabozantinib plus nivolumab and ipilimumab, as well as the updated analysis of avelumab in urothelial carcinoma.Apolo: At the 2017 ESMO Congress, we presented the final results of the phase I cohort of the combination of cabozantinib with nivolumab, and cabozantinib with nivolumab and ipilimumab. The trial is still open, and we have multiple cohorts still enrolling in the expansion cohort, but the phase I findings that we are presenting here have the longest follow-up.

We found very nice activity throughout multiple GU tumors, so this is not only bladder cancer or kidney cancer; it’s all GU tumors, including renal cancer, prostate cancer, and, importantly, rare GU tumors such as squamous cell carcinoma of the bladder, adenocarcinoma of the bladder, testicular cancer, and penile cancer. We saw responses in these rare tumors with the combination.

There were some big results presented at the 2017 ESMO Congress. How do you look at these results in conjunction with your findings?

Can you discuss your findings with avelumab?

With 5 checkpoint inhibitors in the bladder cancer space, how could these results help clinicians pick the right therapy?

One of the things that we focused on during this presentation was safety. We wanted to see if the combination was tolerable and whether there were additive toxicities. We did see additive toxicities that were grade 1/2—predominantly nausea, vomiting, fatigue, and laboratory abnormalities, such as hyperthyroidism. We also saw some grade 1/2 elevation of liver function tests, which was something that we were really worried about. However, they were all very manageable, so that was exciting because if we want to bring this combination forward into larger trials, we need to make sure it is safe. It shows that cabozantinib is active and nivolumab is active…and combining them just makes sense because we want to increase the activity that we are seeing in these patients.We have the updated data from avelumab as monotherapy in patients with metastatic urothelial carcinoma who are refractory to platinum-based chemotherapy. We had 249 patients in the cohort, and [have data at] 20 months’ follow-up. We are seeing durable responses, which is very important. At 1 year, 70% of [responding] patients are still responding. In terms of toxicity, we did not see any more toxicity with the longer follow-up—about 11% grade 3/4 toxicities. This is very consistent with our earlier reports. That’s a good question. I don't know if there is a good algorithm to pick among the 5 checkpoint inhibitors that are approved for metastatic urothelial carcinoma. They are all active; the trial is very little in terms of ORR, overall survival, and progression-free survival, so it is based on availability. But I always say, if possible, enroll in a clinical trial.

There has been a lot mentioned about tumor burden and biomarkers in this space. Could you share your insight on that?

That is the most important thing because, as we try to build on the activity, we are moving toward combination therapies. There are a lot of clinical trials open now; if you can enroll your patient into a clinical trial, we can then learn about the cumulative responses that could potentially occur synergistically with different mechanisms of action. We have seen increased immune/immune combinations, immune/chemotherapy combinations, and then, with our trial, immunotherapy with TKIs.In terms of selecting patients with bladder cancer based on biomarkers, there are a lot of studies going on; there are a lot of things that we are looking at. Mutational burden is one of them, and it does seem to be correlated with overall outcomes. Can we select patients based on this? Not yet. Just like PD-L1, there is also a correlation; we are still trying to figure out the value. Combining biomarkers together may be the key way to select these patients and there are correlations, but we cannot yet use them to select patients for treatment.

References

  1. Nadal R, Mortazavi A, Stein M, et al. Final results of a phase I study of cabozantinib (cabo) plus nivolumab (nivo) and cabonivo plus ipilimumab (Ipi) in patients (pts) with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignancies. In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract 846O.
  2. Apolo AB, Ellerton J, Infante JR, et al. Avelumab treatment of metastatic urothelial carcinoma (mUC) in the phase 1b JAVELIN solid Tumor study: updated analysis with 6 months of follow-up in all patients. In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract 856P.

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