Stemming from the wave of checkpoint inhibitor approvals, multiple trials have begun evaluating immunotherapies in combination with other agents for the treatment of patients with advanced bladder cancer.
Jonathan E. Rosenberg, MD
Stemming from the wave of checkpoint inhibitor approvals, multiple trials have begun evaluating immunotherapies in combination with other agents for the treatment of patients with advanced bladder cancer, according to a presentation by Jonathan E. Rosenberg, MD, at the 18th Annual Meeting of the Society of Urologic Oncology.1
The recent immunotherapy approvals have represented a sea change for many patients with bladder cancer; however, only a proportion derive benefit from these agents as monotherapy. To build upon this, investigators are looking at combinations with chemotherapy, anti-angiogenetic agents, or other immunotherapy agents to increase the impact of these agents.
“Immunotherapy has revolutionized the treatment of advanced urothelial carcinoma,” said Rosenberg, a medical oncologist at Memorial Sloan Kettering Cancer Center. “There have been rapid and dramatic advances in the treatment of locally advanced and metastatic urothelial carcinoma.”
The most potentially impactful phase III trials on the horizon are exploring the combination of immunotherapy with chemotherapy. These trials include the CheckMate 901, IMvigor130, and KEYNOTE-361 trials, which are exploring different checkpoints inhibitor combinations. The CheckMate 901 trial is assessing nivolumab (Opdivo) with ipilimumab (Yervoy) or chemotherapy; IMvigor130 is exploring atezolizumab (Tecentriq) with chemotherapy; and, KEYNOTE-361 is examining pembrolizumab (Keytruda) and chemotherapy. All these trials are currently recruiting (NCT03036098, NCT02807636, NCT02853305).
The already-approved single-agent immunotherapies are also now being assessed with other immune-based agents, particularly those targeting CTLA-4 or IDO1. Results have been seen from the CheckMate 032 trial, which explored nivolumab alone or in combination with ipilimumab, and although the toxicity of this combination is manageable, Rosenberg said, it is higher than that of anti—PD-1/PD-L1 monotherapy, prompting the search to find a less toxic immune-immune combination.
“We’ve seen that these immune-immune combinations hold significant promise with the CTLA-4 and PD-1 combination data,” says Rosenberg. “However, identification of agents with less toxicity in combination is clearly warranted.”
Rosenberg suggested that resistance to PD-1 pathway inhibition may be mediated by IDO1 activity, as IDO1 leads to depletion of tryptophan and increased kynurenine levels resulting in an immunosuppressive tumor microenvironment. This leads to decreased effector T cell function and differentiation of T regulatory cells, Rosenberg said.
The combination of PD-1 and IDO1 inhibition is currently being assessed in several clinical trials. There have been early promising results seen for the combination of the IDO1 inhibitor epacadostat and pembrolizumab in a 40-patient expansion cohort, presented at the ASCO 2017 Annual Meeting.2 The overall response rate (ORR) with the combination was 35%, which included 3 complete responses.
Importantly, the tolerability of the combination appeared similar to PD-1 therapy alone, Rosenberg said. In a pooled analysis of several patients, grade ≥3 treatment-related adverse events were experienced by 18% of patients. The safety profile combined with the promising response rate is worthy of further investigation in a large randomized trial for patients with bladder cancer, he added.
In addition to novel combination approaches, another option to further utilize immunotherapy in bladder cancer is to move these agents earlier in the disease, said Rosenberg. “If stage 0 to 3 tumors are susceptible, perhaps we can increase cure rates,” he said.
Adjuvant trials are currently ongoing, and a randomized phase III study evaluating the addition of immunotherapy to chemoradiation has been proposed to the NCTN. Additionally, multiple trials are enrolling that are testing anti—PD-1/anti–PD-L1 therapy in muscle invasive and non-muscle invasive bladder cancer.
In patients with muscle-invasive or node-positive urothelial cancer who have undergone radiotherapy, 3 studies are currently evaluating the potential impact of immunotherapy. These are the IMvigor010 trial with atezolizumab versus observation (NCT02450331), the CheckMate-274 with nivolumab versus placebo (NCT02632409), and A031501 (conducted by the NCI), which is comparing pembrolizumab with observation (NCT03244384).
Rosenberg said that although the numbers of combinations are daunting, biomarker work on patient samples will hopefully identify targetable resistance mechanisms, creating a more rational approach to combinations. “If we show that we can actually eradicate hypermetastatic disease in patients with locally advanced cancers, we will hopefully be moving the field forward effectively,” he concluded.
Other PD-1/IDO1 combinations are also currently under exploration, namely nivolumab plus BMS986205, which was assessed in a 25-patient multi-cohort phase I/II dose escalation and expansion study (CA017-003). In heavily pretreated patients with bladder cancer, the ORR with this combination was 32%, according to recent findings from the SITC Annual Meeting.