Investigators are testing whether the addition of inhibitors targeting the PD-1 and IDO immune pathways to standard chemotherapy in the neoadjuvant setting will offer superior outcomes for patients with muscle-invasive bladder cancer.
Matthew Galsky, MD
Investigators are testing whether the addition of inhibitors targeting the PD-1 and IDO immune pathways to standard chemotherapy in the neoadjuvant setting will offer superior outcomes for patients with muscle-invasive bladder cancer (MIBC).
The phase 3 ENERGIZE trial (NCT03661320) will evaluate nivolumab (Opdivo), an anti—PD-1 agent, and linrodostat mesylate (BMS-986205), an investigational IDO inhibitor, in conjunction with standard-of-care (SOC) chemotherapy in patients with micrometastatic disease. The 3-arm trial will compare the triplet regimen with nivolumab plus chemotherapy and with chemotherapy alone in an effort to identify the optimal therapeutic approach in MIBC, where disease recurrence is common.
“The likelihood of metastatic recurrence after local treatment for muscle-invasive bladder cancer is about 50%. Many patients will have definitive local therapy, which may include removal of the bladder, but will still have metastatic recurrence and succumb to bladder cancer,” said Matthew Galsky, MD, director of genitourinary medical oncology and the Novel Therapeutics Unit at The Tisch Cancer Institute at Mount Sinai in New York, New York. “This has led to the development of therapies targeting micrometastatic cancer that might or might not be present.”
ENERGIZE seeks to enroll 1200 patients with clinical stage T2-T4a N0 or M0 MIBC. Investigators will administer gemcitabine and cisplatin to patients randomly assigned to the control arm (arm A), whereas patients randomized to 1 of the 2 experimental arms will receive nivolumab and chemotherapy alone (arm B) or combined with linrodostat mesylate (arm C; Figure).
After neoadjuvant therapy, all patients will undergo radical cystectomy (RC), but treatment will continue in only arms B and C. Post RC, patients in arm B will receive nivolumab monotherapy. In arm C, RC will be followed by adjuvant nivolumab and linrodostat mesylate. The coprimary end points are pathological complete response (pCR) and EFS. Secondary end points include overall survival (OS), adverse events (AEs), and serious AEs, among other outcome measures.
Early Signs of Efficacy
The indoleamine 2,3-dioxygenase 1 pathway has been a target of interest in MIBC for several years. In a phase 1/2 trial (NCT02658890), the combination of nivolumab plus linrodostat mesylate demonstrated efficacy with an acceptable safety profile in patients with heavily pretreated solid tumors, including participants with advanced bladder cancer.1
At a median follow-up of 24 weeks, the objective response rate (ORR) among the 27 patients with immunotherapy-naïve advanced bladder cancer was 37%. This included 3 complete and 7 partial responses. The disease control rate was 56%, leading investigators to conclude that the preliminary evidence justified further evaluation of the immunotherapy combination in bladder cancer.1
In recent years, the idea of coadministering an anti—PD-1 agent with an IDO1 inhibitor sparked “a lot of enthusiasm” in MIBC because “the response rates with the combination seemed to be higher than what was historically achieved with PD-1 or IDO1 blockade alone” in several small and uncontrolled studies, according to Galsky.
Figure. Phase 3 ENERGIZE Trial (NCT03661320; Click to Enlarge)
“[These data] dampened the enthusiasm for the approach and, unfortunately, had a rippling effect through clinical trials that led multiple studies that were combining IDO inhibitors with immune checkpoint blockade to be shut down or [scrapped],” Galsky said. “IDO inhibition went from being everyone’s favorite [new] mechanism to being one that no one believed in anymore, and this was all based on 1 major phase 3 study, despite years of science3 suggesting that IDO1 inhibition is an important mechanism.”
Notably, ENERGIZE is “one of the few studies trying to definitively determine whether or not there is a role for IDO inhibition in combination with immune checkpoint blockade,” according to Galsky.
Despite the negative KEYNOTE-252/ ECHO-301 data, the rationale for combining an anti—PD-1 agent with an IDO inhibitor is bolstered by the synergy that can be achieved with nivolumab and linrodostat mesylate. IDO1 is an enzyme that is highly expressed in a variety of malignancies and correlates with poor prognoses due to its immunosuppressive mechanism and promotion of tumor neovascularization.3,4
“We know from multiple types of cancers, both in model systems and in the clinic, that IDO converts tryptophan to kynurenine, and the high levels of kynurenine lead to immunosuppressive effects,” Galsky said.
Kynurenine stimulates tumor regulatory T cells and suppresses effector T-cell proliferation, enabling IDO1-expressing tumors to evade the immune system.1 Linrodostat mesylate offsets this activity by decreasing kynurenine in tumor cells, restoring the functionality of immune cells such as natural killer cells, dendritic cells, and T lymphocytes while reducing the number of tumor-associated regulatory T cells.4,5
Anti—PD-1 therapies such as nivolumab have demonstrated the ability to upregulate IDO1 in multiple malignancies, supporting the use of PD-1 blockade in combination with IDO1-targeted agents.3 In MIBC, tumor PD-L1 expression typically increases following treatment with cisplatin-based neoadjuvant chemotherapy. Adding a PD-1/PD-L1—directed agent to neoadjuvant chemotherapy may lead to greater control of this expression.3 Further, although IDO1 inhibitors have not demonstrated clinical activity as single agents in advanced solid tumors, preclinical models suggest that the integration of IDO1 inhibition into a chemotherapy regimen augments the anticancer effect.3
Testing new therapies is critical to moving the needle in MIBC because, in contrast with non-MIBC, “there has not been an improvement in the treatment of [the disease] in decades,” Galsky said. “This is 1 of a series of trials that will, hopefully, change that.”
Treatment for MIBC, which accounts for 20% to 30% of urothelial carcinoma cases, traditionally consists of neoadjuvant cisplatin- based followed by RC. Upfront RC may also be pursued, in place of chemotherapy.5
Recurrence is common among patients with MIBC, including those who undergo RC, and adjuvant cisplatin-based chemotherapy does not sufficiently extend survival in patients with recurrence.6 Chemotherapy confers a modest benefit to the 30% to 35% of patients who achieve a pCR that translates to improved survival.3 Consequently, more efficacious interventions are needed.
Importantly, immunotherapy has advanced the treatment paradigm in non-MIBC and is being investigated in the MIBC neoadjuvant setting, either alone or with chemotherapy, in several small studies, according to Galsky. For example, the phase 2 PANDORE trial (NCT03212651) is evaluating neoadjuvant pembrolizumab monotherapy in a maximum of 41 patients with MIBC who are not candidates for cisplatin-based chemotherapy.
The PECULIAR study (NCT03832673) has yet to begin enrollment but is designed to accrue up to 38 patients with MIBC. Participants will receive pembrolizumab and epacadostat prior to RC. The PD-L1 antibody atezolizumab (Tecentriq) is also being explored in several trials, including in combination with cabozantinib (Cabometyx) in a phase 2 study (NCT04289779).
These investigations will build on existing data that suggest a benefit with single-agent neoadjuvant immunotherapy in MIBC, said Galsky. Notably, findings from the phase 2 PURE-01 study (NCT02736266) of neoadjuvant pembrolizumab in 50 patients with MIBC showed that single-agent immune checkpoint blockade induced a pCR, defined as pT0, in 42% of patients (95% CI, 28.2%-56.8%). The percentage of patients who achieved pT0 after 3 cycles of pembrolizumab and subsequent RC was “unprecedented,” investigators said.6
Further, pT0 occurred in 54.3% of patients with a PD-L1 combined positive score greater than or equal to 10% versus 13.3% of patients with a score less than 10%, leading investigators to conclude that neoadjuvant pembrolizumab might be most advantageous in patients who are PD-L1—positive or who have a high tumor mutation burden, given that the top scores of pre-therapy burden were associated with pT0.6
The viability of single-agent neoadjuvant immune checkpoint blockade in MIBC is also supported by results from the phase 2 ABACUS trial (NCT02662309), which evaluated 2 cycles of atezolizumab prior to RC in 95 patients. The study met its primary end point with a pCR of 31% (95% CI, 21-41). Importantly, no new safety signals were identified with neoadjuvant atezolizumab, which did not complicate RC.7
In contrast with PURE-01, PD-L1 expression did not correlate with outcome (P >.05). However, high presence of intraepithelial CD8-positive cells was associated with immunotherapeutic response: the pCR was 40% (95% CI, 26%-57%) in patients with these cells versus 20% (95% CI, 9%-35%) in participants without them (P <.05), and the 1-year relapse-free survival rate was 85% (95% CI, 67%-94%) in the CD8-positive population.7
With a different trial design, ENERGIZE will answer a clinical question that could have actionable impact: Does dual anti—PD-1 and IDO1 inhibition have a role in the MIBC treatment landscape?
Although many clinical trials have suspended enrollment due to health concerns related to the coronavirus disease 2019 pandemic, ENERGIZE remains open for enrollment and continues to accrue patients across many of its approximately 180 locations worldwide, including sites in the United States.
However, the excitement that initially surrounded IDO1 inhibition across disease settings swiftly waned with the release of data from the negative phase 3 KEYNOTE-252 trial/ECHO-301 (NCT02752074) of epacadostat and pembrolizumab (Keytruda), also an anti—PD-1 antibody, in patients with unresectable or metastatic melanoma. This trial enrolled 706 patients, 354 of whom received the doublet therapy; the remaining 352 were treated with pembrolizumab monotherapy. At 12 months, the OS rate was 74% in both arms. The ORR was 34.2% with the combination and 31.5% with pembrolizumab monotherapy.2