Sumit K. Subudhi, MD, PhD
The combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) demonstrated activity in a biomarker-enriched population of patients with metastatic castration-resistant prostate cancer (mCRPC); however, researchers need to refine the toxicity profile, said Sumit K. Subudhi, MD, PhD.
In the phase II CheckMate-650 trial (NCT02985957), results of which were presented at the 2019 Genitourinary Cancers Symposium, overall response rates (ORR) with the immunotherapy combination were 25% in asymptomatic and minimally symptomatic patients who progressed after second-generation hormonal therapy and had not received chemotherapy (cohort 1) and 10% in patients who progressed after taxane-based chemotherapy (cohort 2).
In the trial, patients received nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks for 4 doses, then nivolumab at 480 mg every 4 weeks. Results showed that in both cohorts, the ORR was higher in patients with PD-L1 expression ≥1%, DNA damage repair, homologous recombination deficiency, and tumor mutational burden (TMB) above the median (74.5 mutations/patient). Of all prostate-specific antigen (PSA)-responding patients, 4 had PSA <0.2 ng/mL.
Notably, the ORR was 60% for the TMB-high patients in cohort 1 and 50% for these patients in cohort 2. In cohort 1, patients with PD-L1 expression ≥1% had an ORR of 33.3% compared with 19% in cohort 2.
However, toxicities associated with the regimen appeared to be a challenge, said Subudhi, a co-author of the trial. Grade 3/4 adverse events (AEs) occurred in 42.2% and 53.3% of patients in cohorts 1 and 2, respectively. Further, one grade 5 event was observed in each cohort.
In an interview with OncLive
, Subudhi, an associate professor in the Department of Genitourinary Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, discussed the promise of the combination of nivolumab and ipilimumab in patients with mCRPC and the challenges that lie ahead with this treatment approach.
OncLive: What was the rationale for the CheckMate-650 trial?
: Checkpoint inhibitors as monotherapy have had very limited efficacy in mCRPC. In fact, the anti–PD-1 [agent] nivolumab had [failed to show] responses in a phase I study. There are also 2 phase III trials [exploring the use of] ipilimumab in mCRPC and neither have shown a survival benefit. Our group at The University of Texas MD Anderson Cancer Center wanted to understand why this was occurring, when in other cancers, checkpoint inhibitors have had great impact. What we found is that when you look at the tumor microenvironment of prostate cancer prior to treatment, there are very few T cells present, unlike [what is seen with] other diseases—such as lung cancer and melanoma. However, when you give 2 doses of a CTLA-4 inhibitor, you can drive T cells into the cancer.
What we found is that in prostate cancer, the tumor microenvironment adapts and upregulates other immune checkpoints, such as PD-L1, preventing those T cells that have come in from actually killing the cancer. In our preclinical models, we combined both PD-1 and CTLA-4 [inhibitors] and saw pretty amazing durable responses. That led to the design of this study, where we combined nivolumab with ipilimumab. As we had predicted, we were able to see a subset of patients really develop meaningful clinical responses. A subset of patients developed undetectable PSA levels that are longer than 1 year in duration.
Could you expand on the findings that were presented at the 2019 Genitourinary Cancers Symposium?
We had 2 cohorts of patients. Cohort 1 was comprised of patients who did not receive chemotherapy but received at least 1 prior line of hormonal therapy. Cohort 2 was comprised of patients who did receive taxane-based chemotherapy, such as docetaxel. We found that the response rate in patients with measurable disease was 25% in cohort 1; it was approximately 10% in cohort 2. This [finding] is pretty striking because of the durability of these responses.
The other thing that I wanted to point out was that toxicity was an issue. Moving forward, we will be looking to change the dosing or the scheduling of the drug so that we can try to increase the number of patients who are getting these agents, in the hopes of increasing response rates. We saw high rates of diarrhea, which is something that we commonly see in other diseases treated with immunotherapy.
What are the next steps with this research?
The next steps are to confirm the biomarker analysis, in which we saw that TMB was associated with responses. In this cohort of patients, the median TMB was 74.5 per patient. Patients who had median levels above 74.5 were more likely to respond. We need to confirm that [finding] in a larger cohort.
Where do you ultimately see this combination fitting into the treatment paradigm?
I believe that we will be able to identify a subset of patients who will respond to this combination. We will also be able to identify resistance mechanisms that will require additional agents to be added to nivolumab plus ipilimumab. One of the things we always have to worry about when adding more agents to any regimen is the toxicity. Sequencing [therapies] will be important. You may want to drive T cells to a cold tumor like prostate cancer by giving ipilimumab, then follow it up with nivolumab in combination with another drug.
How important would this addition be to the field, even if it benefits a small subset of patients?
Right now, we treat all patients with mCRPC the same exact way, as if there is no disease heterogeneity. We know that there are definitely different biological subsets—tumors that are hormone sensitive, hormone resistant, and several tumors in between. We need to identify these patients a little bit better so that we can allocate therapies better.
What does the outlook for patients with mCRPC look like today versus a few years ago?
Today, there is a lot more hope and promise for patients. In fact, if you speak to any of the patients who are having durable responses, they would tell you that their life has changed. Their perspective on their cancer has changed, so it is really exciting.
Sharma P, Pachynski R, Narayan V, et al. Initial results from a phase II study of nivolumab (NIVO) plus ipilimumab (IPI) for the treatment of metastatic castration-resistant prostate cancer (mCRPC; CheckMate 650). J Clin Oncol. 2019;37(suppl 7S; abstr 142).