Andrea Apolo, MD, discusses a pooled analysis of the phase Ib Javelin Solid Tumor study, and a phase I study of cabozantinib, nivolumab, and ipilimumab.
Andrea Apolo, MD
In May 2017, avelumab (Bavencio) was approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma.
Since that approval, the PD-L1 inhibitor has been evaluated in larger cohorts to observe efficacy and tolerability—specifically, in the Javelin Solid Tumor study, which was the pivotal study that led to the FDA approval. And although clinical activity is promising with the single agent, Andrea Apolo, MD, says that clinical trials in bladder cancer are moving toward combinations, which she says will improve on the already impressive progress made so far with immunotherapy in this disease.
Combinations of immunotherapy are showing activity in tumors that lack standard of care. In a phase I study, combinations of cabozantinib (Cabometyx) plus nivolumab (Opdivo), and cabozantinib plus nivolumab and ipilimumab (Yervoy), were active and well tolerated with no dose-limiting toxicities in patients with refractory metastatic urothelial carcinoma and other rare genitourinary malignancies, such as penile cancer.
In an interview with OncLive at the 2017 ASCO Annual Meeting, Apolo, chief of the bladder cancer section of the Genitourinary Malignancies Branch at the National Cancer Institute, discussed the pooled analysis of the phase Ib Javelin Solid Tumor study,1 and the phase I study of cabozantinib, nivolumab, and ipilimumab.2 Apolo is the lead investigator on both studies.Apolo: This year at ASCO 2017 we presented the updated pooled analysis of avelumab in patients with metastatic urothelial carcinoma. On May 9 of this year, the FDA approved avelumab for the treatment of patients with metastatic urothelial carcinoma refractory to chemotherapy. The analysis is pooled because it is 2 different cohorts. We have the 44-patient cohort, and then we have a 200-patient cohort. So, there are 250 patients that we have data on with a 6-month follow-up. We have 161 patients that we have response rate and efficacy data on. The overall response rate is 17.4%. What is really exciting about this response rate, is at the time of data cutoff, 82% of the patients were still responding. So, we see very durable responses with avelumab therapy. No, they are the same—they are both second-line patients. The first one was just an initial cohort to see what the efficacy was, and when we saw there was efficacy we expanded it to a larger cohort to confirm the efficacy. The nice thing is that in the larger cohort, the efficacy is the same. We did look at the PD-L1 data in terms of the tumor staining, and there was a higher response rate for patients who were PD-L1 positive, 25% versus 13%—this was not statistically significant, but there was a trend toward significance. Now with the new approval of avelumab, and a lot of other immunotherapy checkpoint inhibitor agents in bladder cancer, I think it is such a great opportunity to expand the science and do better because although we are seeing very nice responses—about 15% to 20%. We still can do better. I think that is what the goal is in a lot of clinical trials looking at combination regimens to see if we can approve upon what we have so far. PD-L1 is not the perfect biomarker, it has a lot of issues in terms of the variability of the different assays and the different cutoff. But I think now, as we understand that, and we try to improve upon the assay—perhaps in larger cohorts—we will see the real value and learn how to assess the real value of PD-L1 as a marker in this patient population.Avelumab is active in patients with metastatic cancer, and the responses are durable, so that is very exciting. It now joins 4 other agents that are also active in bladder cancer, so now we have more drugs and that is terrific for our patients. Another study is the combination of cabozantinib and nivolumab, and cabozantinib, nivolumab, and ipilimumab in patients with metastatic urothelial carcinoma and other genitourinary tumors. We have enrolled 66 patients, but have data on 46 patients, with a median follow-up of 12.4 months.
We are seeing very impressive response rates. The overall response rate for the entire cohort was 37%. When we look at the specific bladder cancer cohort, we see an overall response rate of 44%. Very exciting results with the combination. In terms of the median overall survival, it hasn’t been reached yet, so that is terrific, and the progression-free survival is 6.4 months that we have seen.In terms of the side effects that we have seen with the combination of cabozantinib plus nivolumab and cabozantinib plus nivolumab plus ipilimumab, we see the typical side effects that we see with cabozantinib and the typical side effects that we see with nivolumab and ipilimumab. One of the great things is that we have not seen synergy among the toxicities, and that 1 thing that we were initially worried about as a phase I study, but the regimen has actually been pretty well tolerated. We have come up with a recommended phase II dose of cabozantinib at 40 mg, nivolumab at 3 mg/kg, and ipilimumab at 1 mg/kg.
One of the things that is really exciting is that we have seen responses in rare genitourinary tumors like kidney sarcomatoid, and in bladder, we have seen responses in adenocarcinoma urachal and squamous cell carcinoma of the bladder. We have also seen responses in penile cancer.
The next step is to move [the] cabozantinib, nivolumab, and ipilimumab [regimen] into larger cohorts of study both in bladder and kidney cancer, and we are also planning to expand it into a large study in rare genitourinary tumors. Absolutely, especially because a lot of these rare tumors don’t have standard of care, so the fact that we are seeing activity is very exciting.