Abstract
Purpose:
IDO1 induces immune suppression in T cells through L-tyrptophan (Trp) depletion and kyneurinine (Kyn) accumulation in the local tumor microenvironment, suppressing effector T cells and hyperactivating Tregs. Navoximod is an investigational small molecule inhibitor of IDO1. This Phase I study evaluated safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of navoximod in combination with atezolizumab, a PD-L1 inhibitor, in patients with advanced cancer.
Experimental Design:
The study consisted of a 3+3 dose-escalation stage (n=66) and a tumor-specific expansion stage (n=92). Navoximod was given orally every 12 hours (q12h) continuously for 21 consecutive days of each cycle with the exception of Cycle 1, where navoximod administration started on Day −1 to characterize PK. Atezolizumab was administered by IV infusion q3w on Day 1 of each cycle.
Results:
Patients (n=157) received navoximod at 6 dose levels (50–1000 mg) in combination with atezolizumab. MAD was 1000 mg BID; the MTD was not reached. Navoximod demonstrated a linear PK profile, and plasma Kyn generally decreased with increasing doses of navoximod. The most common treatment-related AEs were fatigue (22%), rash (22%), and chromaturia (20%). Activity was observed at all dose levels in various tumor types (melanoma, pancreatic, prostate, ovarian, HNSCC, cervical, neural sheath, NSCLC, TNBC, RCC, UBC): 6 (9%) dose escalation patients achieved PR, 10 (11%) expansion patients achieved PR or CR.
Conclusions:
The combination of navoximod and atezolizumab demonstrated acceptable safety, tolerability and PK for patients with advanced cancer. Although activity was observed, there was no clear evidence for benefit of adding navoximod to atezolizumab.
Introduction
Indoleamine 2,3-dioxygenase 1 (IDO1) is a cytosolic enzyme that catalyzes the rate-limiting step of L-tryptophan (Trp) metabolism to kynurenine (Kyn) (Munn and Mellor, 2016). The main role of IDO1 is the regulation of acquired local and peripheral immune tolerance in normal and pathological scenarios (Uyttenhove et al. 2003). In cancer, IDO1 induces immune suppression in T cells through at least two distinct mechanisms. Trp depletion in the local tumor microenvironment activates a starvation response in T cells that impairs their function. Additionally, accumulation of Kyn, an endogenous ligand for the aryl hydrocarbon receptor, acts to suppress effector T cells and hyperactivate regulatory T cells (Tregs). Together, these effects lead to decreased inflammation and immune responsiveness towards tumors (Desvignes et al. 2009; Favre et al. 2010).
Increased expression of IDO1 in a variety of human tumors is observed and often associated with worse clinical outcome (Brochez et al. 2017). Mechanistically, inhibition of IDO1 alone is expected to modulate the microenvironment to potentiate the action of immune effectors but is not expected to kill tumor cells directly, nor initiate a de novo anti-tumor immune response (Munn et al. 2016). In the clinic, IDO1 inhibition alone has little anticancer effect in a majority of patients (Li et al. 2017, Prendergast et al. 2017). However, early phase studies demonstrating encouraging response rates and durability of responses suggested that the addition of IDO1 inhibitors to programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibition may enhance the efficacy of checkpoint blockade alone (Gangadhar et al. 2017, Lara et al. 2017, Perez et al. 2017, Smith et al. 2017).
Navoximod (GDC-0919; previously NLG919) is an investigational small molecule inhibitor of IDO1 with a potency of 75–90 nM for IDO1 in cell-based assays (Mautino et al. 2014). In preclinical models, combination treatment of navoximod with anti-PD-L1 more effectively activates intratumoral CD8+ T cells and inhibits tumor growth compared to either single agent alone (Spahn et al. 2015). The open-label Phase 1a clinical study of navoximod in 22 patients with solid tumors demonstrated that navoximod was generally well-tolerated, and as expected had limited clinical activity, as a single agent (Nayak et al. 2018). The PD-L1 checkpoint inhibitor, atezolizumab, has been approved in the US and EU as a single agent for the treatment of non-small cell lung cancer (NSCLC) and urothelial bladder cancer (UBC). In this Phase 1 study, we examined the combination of navoximod with atezolizumab for the first time as treatment for patients with advanced cancer.
Materials and Methods
Study design
This Phase Ib study was an open-label, multicenter, dose-escalation and expansion study of navoximod in combination with atezolizumab in adult patients with locally advanced or metastatic solid tumors (Figure 1). The primary objectives of the study were to evaluate the safety and tolerability of navoximod and atezolizumab when administered in combination; secondary and exploratory objectives included assessments of immunogenicity, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary signs of anti-tumor activity.
Figure 1.
Study design.
a Backfill patients were enrolled after each preceding dose level cleared the DLT window. Optional biopsies were collected at baseline and 2–3 weeks after Cycle 1, Day 1.
bSingle agent run-in navoximod (Biopsy A) or atezolizumab (Biopsy B) in patients with either melanoma, HNSCC, gastric, ovarian, cervical, Merkel cell, or endometrial cancer.
NSCLC: non-small cell lung carcinoma; UBC: urothelial bladder cancer; RCC: renal cell carcinoma; TNBC: triple negative breast cancer; CIT: immunotherapy.
The dose escalation stage of the study used a standard 3+3 design to evaluate escalating doses of navoximod (50–1000 mg) with a fixed dose of atezolizumab (1200 mg), both provided by Genentech, Inc. Navoximod was administered orally every 12 hours (q12h) continuously for 21 consecutive days of each cycle (Days 1–21) with the exception of Cycle 1, where navoximod administration started on Day −1 to characterize PK. Atezolizumab was administered by IV infusion q3w on Day 1 of each cycle. The dose limiting toxicity (DLT) assessment window was 22 days (Days −1 to 21 of Cycle 1) with DLTs defined as any of the following treatment-related toxicities: Grade ≥ 3 non-hematological, non-hepatic toxicity; severe hematological toxicity (Grade ≥ 4 neutropenia, Grade ≥ 3 febrile neutropenia, Grade ≥ 4 anemia, Grade ≥ 4 thrombocytopenia, or Grade 3 thrombocytopenia associated with clinically significant bleeding); severe hepatic toxicity (Grade ≥ 3 elevation of ALT, AST, or serum total bilirubin; concurrent elevation of ALT or AST > 3 × the upper limit of normal (ULN) and total bilirubin 2 × ULN).
If 1 out of 3 patients experienced a DLT within the first cycle, 3 additional patients were enrolled at that dose level. If a DLT was observed in ≥ 2 patients at any dose level, escalation ceased and the previous dose was declared the maximum tolerated dose (MTD). To acquire additional safety and PD data to more fully inform the dose selection for the expansion stage of the study, additional “backfill” patients were enrolled at dose levels that did not exceed the MTD, but were not included in the DLT-evaluable population.
In the expansion stage, select indications were evaluated (Figure 1). Patients enrolled in the expansion cohorts were given 600 mg or 1000 mg PO BID of navoximod in combination with 1200 mg IV q3w of atezolizumab.
Treatment beyond radiographic progression per RECIST v1.1 was permitted in the absence of evidence of unequivocal progression of disease, decline in ECOG performance status, or tumor progression at critical anatomical sites in patients who provided written informed consent. No intrapatient dose escalation was permitted.
Institutional Review Board approvals for the study protocol, amendments, and informed consent documents were obtained prior to study initiation. Study procedures were conducted in accordance with the Declaration of Helsinki. The ClinicalTrials.gov identifier for the Phase 1b study (GO29779) was NCT02471846.
Patient eligibility
Eligible patients were ≥ 18 years old with histologically documented, incurable, locally advanced or metastatic solid tumors, had Eastern Cooperative Oncology group (ECOG) performance status of 0–1, adequate hematologic and end organ function, and measurable disease per RECIST v1.1. Patients with risk of autoimmune disease or history of infection with HIV, Hepatitis B or C were excluded. Also excluded were patients who received prior treatment with T cell co-stimulatory receptor agonist antibodies or IDO/TDO inhibitors; and concomitant immunosuppressive medication, concomitant acetaminophen at doses ≥ 1000 mg per day, or drugs associated with Torsades de Pointes, which could not be safely discontinued.
Patients enrolled in the dose escalation stage of the study were allowed prior treatment with PD-1, PD-L1, CTLA4, or other checkpoint inhibitors, provided these were discontinued within a specified period before study start. Patients in the expansion stage of the study were not allowed prior treatment with checkpoint inhibitors except for patients enrolled in the relapsed NSCLC cohort, which specifically required patients to have achieved best response of CR/PR or SD on most recent therapy with PD-1/PD-L1 inhibitors. All patients enrolled in the expansion stage were required to provide tumor tissue that was evaluable for PD-L1 expression, and enrollment was managed to ensure that fewer than 25% of the patients were PD-L1 negative.
Safety assessments
The safety population included all patients who received at least one dose of navoximod or atezolizumab. Safety assessments included physical examination, vital sign measurements, clinical laboratory testing, triplicate 12-lead electrocardiogram, and monitoring and recording of adverse events (AEs) including serious and non-serious AEs of special interest (AESI). AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. The adverse event reporting period extended for 60 days after the last dose of navoximod and/or atezolizumab or prior to the initiation of a new systemic anti-cancer treatment whichever occurred first. An Internal Monitoring Committee reviewed the cumulative safety profile at regular intervals following the start of the expansion stage.
Pharmacokinetic assessments
Blood samples were collected for navoximod PK evaluation before and up to 8 hours after single and multiple twice-daily doses of navoximod. Plasma concentrations of navoximod were determined using a validated liquid chromatographic-tandem mass spectrometry (LC/MS-MS) method with a lower limit of quantitation of 1 ng/ml, and PK parameters were estimated using non-compartmental analysis (Phoenix WinNonlin 6.4; Cetara, Princeton, NJ).
Evaluation of tumor response
CT or MRI studies were obtained at screening, and at approximately every 6 weeks for 24 weeks, and every 12 weeks thereafter until disease progression or loss of clinical benefit. Objective response was determined by the investigators according to RECIST v1.1.
Biomarker assessments
Blood was collected to monitor changes in plasma Kyn levels as a peripheral biomarker of IDO1 activity. Samples were collected at the same timepoints as PK assessments, with another sample drawn at the time of radiographic progression for patients enrolled in mandatory biopsy cohorts. Validated LC/MS-MS assays were used to measure the concentration of Kyn in plasma samples, with a lower limit of quantitation of 25 ng/mL. Samples were analyzed at Covance Laboratories.
IDO1 and PD-L1 were evaluated in formalin-fixed and paraffin-embedded tumor samples using monoclonal antibody clones SP260 (Spring) for IDO1 and SP142 (Spring) for PD-L1 in validated immunohistochemistry (IHC) assays. IDO1 and PD-L1 expression was evaluated both on tumor cells (proportion of positive cells estimated as the percentage of total tumor cells) and tumor-infiltrating immune cells (percentage of positive tumor-infiltrating immune cells occupying the tumor) as previously described for PD-L1 (Herbst et al. 2014). CD8 IHC using monoclonal antibody clone SP16 (Epitomics) was also performed as previously described (Herbst, 2014).
Statistical analyses
In this study, no formal statistical hypotheses were tested, and all analyses were descriptive and exploratory. Design considerations were not made with regard to explicit power and type I error, but rather to obtain preliminary safety, activity, PK, and PD information. All patients who received ≥ 1 dose of navoximod or atezolizumab were included in the safety and activity analyses.
Results
Patient characteristics
From July 2015 to July 2017, 158 patients were enrolled from 18 sites in the United States, Spain, France, and South Korea. Patient demographics and baseline characteristics are summarized in Table 1. The patient population in the dose escalation stage was heterogeneous, including over 15 different indications. Patients with an ECOG status of 1 comprised 49% and 72% of the dose escalation and dose expansion populations, respectively. Both the dose escalation and expansion stage patients were heavily pre-treated.
Table 1.
Patient baseline and disease characteristics (intent to treat population).
| Variable | Dose Escalation (n=66)a | Dose Expansion (n=92) | All Patients (N=158) |
|---|---|---|---|
| Age (yr), median (range) | 61 (31–80) | 59 (33–78) | 59 (31–80) |
| Sex | |||
| Female | 43 (65%) | 48 (52%) | 91 (58%) |
| Male | 23 (35%) | 44 (48%) | 67 (42%) |
| ECOG performance status | |||
| 0 | 33 (51%) | 25 (28%) | 58 (37%) |
| 1 | 32 (49%) | 65 (72%) | 97 (63%) |
| Race | |||
| Black or African American | 2 (3%) | 1 (1%) | 3 (2%) |
| White | 60 (91%) | 51 (55%) | 111 (70%) |
| Asian | 2 (3%) | 36 (39%) | 38 (24%) |
| Unknown | 2 (3%) | 4 (4%) | 6 (4%) |
| Most common tumor types | |||
| Lung (NSCLC) | 1 (2%) | 42 (46%) | 43 (27%) |
| Breastb | 13 (20%) | 12 (13%) | 25 (16%) |
| Ovary | 8 (12%) | 7 (8%) | 15 (10%) |
| Bladder | 3 (5%) | 7 (8%) | 10 (6%) |
| Kidney | 2 (3%) | 7 (8%) | 9 (6%) |
| Endometrial | 5 (8%) | 2 (2%) | 7 (5%) |
| Cervical | 4 (6%) | 2 (2%) | 6 (4%) |
| Gastric | 2 (3%) | 4 (4%) | 6 (4%) |
| Head and neck | 3 (5%) | 3 (3%) | 6 (4%) |
| Colon | 4 (6%) | 0 (0%) | 4 (3%) |
| GE junction | 3 (5%) | 1 (1%) | 4 (3%) |
| Melanoma | 2 (3%) | 2 (2%) | 4 (3%) |
| No. prior systemic therapies, median (range) | 3.0 (1.0–11.0) | 3.0 (1.0–17.0) | 3.0 (1.0–17.0) |
| Patients with prior immunotherapy | 5 (8%) | 17 (19%) | 22 (14%) |
NSCLC, non-small cell lung cancer; GE, gastroesophageal.
Includes backfill patients;
TNBC (n=17), ER+/PR+/HER2− (n=4), PR+/ER−/ HER2− (n=1), ER+/ HER2−/PR unknown (n=1), ER/PR/HER2 status unknown (n=2)
As of November, 2017, 151 (96%) patients discontinued from navoximod treatment, and 139 (88%) patients discontinued from atezolizumab treatment, primarily due to disease progression (78% and 93%, respectively). Patients were on navoximod and atezolizumab treatment for a median of 51 days (range 1–713) and 56 days (range 1–693), respectively.
Safety and tolerability
Navoximod given in combination with atezolizumab was generally well-tolerated. The MTD of navoximod in combination with atezolizumab was not identified. There was a single DLT of Grade 3 sepsis syndrome at the 200 mg dose level considered to be related to both study drugs.
There was no clear relationship between dose and either incidence or severity of AEs. Most treatment related (Table 2a) AEs were Grade 1 or 2, with the most common being fatigue, rash, and chromaturia. Grade ≥ 3 treatment-related AEs (Table 2b) were experienced by 35 patients (22%), with the most common being rash (14 patients, 9%). Overall, treatment related serious AEs and discontinuations due to treatment related AEs were reported in 10% and 9% patients, respectively.
Table 2.
(A) Treatment-related all Grade AEs in ≥ 5% of patients receiving 1200 mg atezolizumab in combination with navoximod (safety population). (B) Treatment-related Grade ≥ 3 AEs in ≥ 2 patients receiving 1200 mg atezolizumab in combination with navoximod (safety population).
| Navoximod 50 mg (n=6) | Navoximod 100 mg (n=7) | Navoximod 200 mg (n=12) | Navoximod 400 mg (n=6) | Navoximod 600 mg (n=80) | Navoximod 1000 mg (n=46) | All Patients (N=157) | |
|---|---|---|---|---|---|---|---|
| Any treatment-related adverse event | 5 (83%) | 5 (71%) | 9 (75%) | 4 (67%) | 64 (80%) | 31 (67%) | 118 (75%) |
| Fatigue | 3 (50%) | 3 (43%) | 2 (17%) | 3 (50%) | 13 (16%) | 11 (24%) | 35 (22%) |
| Rasha | 1 (17%) | 1 (14%) | 1 (8%) | 1 (17%) | 20 (25%) | 11 (24%) | 35 (22%) |
| Chromaturia | - | - | 2 (17%) | - | 19 (24%) | 11 (24%) | 32 (20%) |
| Decreased appetite | 1 (17%) | 1 (14%) | 2 (17%) | 1 (17%) | 12 (15%) | 2 (4%) | 19 (12%) |
| Nausea | 1 (17%) | 3 (43%) | - | 1 (17%) | 9 (11%) | 5 (11%) | 19 (12%) |
| Vomiting | 1 (17%) | 2 (29%) | 1 (8%) | - | 8 (10%) | 1 (2%) | 13 (8%) |
| Asthenia | - | - | - | - | 8 (10%) | 4 (9%) | 12 (8%) |
| AST Increased | 1 (17%) | - | 3 (25%) | - | 6 (8%) | 1 (2%) | 11 (7%) |
| Diarrhea | 1 (17%) | - | 1 (8%) | 1 (17%) | 6 (8%) | 1 (2%) | 10 (6%) |
| Anemia | - | 1 (14%) | 2 (17%) | - | 4 (5 %) | 2 (4%) | 9 (6%) |
| Pyrexia | 1 (17%) | - | 2 (17%) | 1 (17%) | 1 (1%) | 4 (9%) | 9 (6%) |
| Hypothyroidism | - | - | 1 (8%) | 1 (17%) | 4 (5 %) | 1 (2%) | 7 (5%) |
| Infusion-related reaction | - | - | 1 (8%) | 1 (17%) | 1 (1%) | 4 (9%) | 7 (5%) |
| Navoximod 50 mg (n=6) | Navoximod 100 mg (n=7) | Navoximod 200 mg (n=12) | Navoximod 400 mg (n=6) | Navoximod 600 mg (n=80) | Navoximod 1000 mg (n=46) | All Patients (N=157) | |
|---|---|---|---|---|---|---|---|
| Any treatment-related Grade ≥ 3 adverse event | - | 1 (14%) | 3 (25%) | 1 (17%) | 17 (21%) | 13 (28%) | 35 (22%) |
| Rasha | - | - | 1 (8%) | - | 4 (5%) | 9 (20%) | 14 (9%) |
| Fatigue | - | - | - | 1 (17%) | 1 (1%) | 1 (2%) | 3 (2%) |
| Anemia | - | - | - | - | - | 2 (4%) | 2 (1%) |
| Hepatitisb | - | - | 1 (8%) | - | 2 (3%) | - | 3 (2%) |
| Hyperlipasaemia | - | - | - | - | 2 (3%) | - | 2 (1%) |
| Pneumonitis | - | - | - | - | 2 (3%) | - | 2 (1%) |
| Thrombocytopenia | - | - | - | - | - | 2 (4%) | 2 (1%) |
Rash includes preferred terms of rash, rash maculo-papular, rash erythematous, rash macular, and rash generalized.
Includes preferred terms of autoimmune hepatitis and hepatitis.
One death was attributed to study treatment, occurring in a patient with metastatic prostate cancer and a history of partial vocal cord paralysis. Twenty-three days following treatment discontinuation, the patient experienced Grade 4 pneumonitis which improved yet was subsequently followed by Grade 5 respiratory failure. Confounders included possible aspiration.
Pharmacokinetics
Navoximod PK evaluations were conducted following the administration of single and multiple oral doses (50–1000 mg BID). Navoximod was rapidly absorbed (median Tmax approximately 1 hour [range: 0.25–4 hours]) and demonstrated dose-proportional and linear PK at the evaluated dose levels (Figure 2). The PK of navoximod when given in combination with atezolizumab was consistent with single-agent PK observations (Nayak-Kapoor et al., 2018 in revision). Atezolizumab PK in combination with navoximod was consistent with single agent observations (data not shown).
Figure 2.
Navoximod plasma concentrations following multiple BID doses. Single dose (SD) and multiple dose (MD) pharmacokinetic parameters for navoximod.
Cmax = maximum observed concentration; tmax = time of maximum observed concentration;
AUC0–8 = area under the curve, measured from 0 to 8 hours post-navoximod dose;
t1/2 = half-life; Geometric mean (geometric CV%) results are presented unless otherwise indicated
aMedian (minimum, maximum) results are presented for tmax
Anti-tumor activity
In the dose escalation stage, 6 of 66 (9%) patients (melanoma, pancreatic, prostate, ovarian, HNSCC and cervical cancer) achieved a partial response (PR), and 11 (17%) patients achieved a best overall response of stable disease (SD). The response rate was slightly higher in patients with PD-L1 expressing (4/30, 13%) vs. PD-L1 negative tumors (2/29, 7%) (Figure 3). At data cutoff, 5 patients remain active and have exceeded 1 year of study treatment.
Figure 3.
Time on study treatment for dose escalation patients.a
PDL1, programmed cell death ligand-1; IC, tumor-infiltrating immune cell; TC, tumor cell; BOR, best overall response.
a BOR for PD-L1 positive patients (n=30): PR 4 pts (13%), SD 6 pts (20%), PD 19 pts (63%);
BOR for PD-L1 negative patients (n=29): PR 2 pts (7%), SD 4 pts (14%), PD 23 pts (79%);
BOR for all patients (n=66) regardless of PD-L1 status: PR 6 pts (9%), SD 11 pts (17%), PD 47 pts (71%).
In the expansion stage where all patients were PD-L1/PD-1 treatment naïve, with the exception of those enrolled in the NSCLC relapsed cohort, there were 10 responders (Table 3). Of the 3 RCC responders, 2 patients had received at least 3 different prior lines of therapies in the metastatic setting before entering this study. Of the 3 UBC responders, 1 patient had received at least 3 different prior lines of therapies in the metastatic setting before entering this study.
Table 3.
Efficacy and PD-L1 IHC in expansion patients.
| NSCLC (CIT naïve) | NSCLC (relapsed) | TNBC (CIT naïve) | RCC (CIT naïve) | UBC (CIT naïve) | Biopsy A (CIT naïve) | Biopsy B (CIT naïve) | All Patients | |
|---|---|---|---|---|---|---|---|---|
| ORR in all patients | n=26 | n=16 | n=11 | n=7 | n=8 | n=11 | n=12 | n=91 |
| ORR in PDL1 IHC 1/2/3 patients | n=14 | n=11 | n=8 | n=7 | n=6 | n=6 | n=8 | n=60 |
| ORR in PDL1 0 patients | n=11 | n=4 | n=3 | n=0 | n=0 | n=5 | n=4 | n=27 |
| ORR in IDO1 IHC 1/2/3 patients | n=17 | n=14 | n=8 | n=7 | n=6 | n=8 | n=8 | n=68 |
| ORR in IDO1 0 patients | n=8 | n=1 | n=3 | n=0 | n=0 | n=3 | n=4 | n=19 |
NSCLC, non-small cell lung cancer; TNBC, triple-negative breast cancer; RCC, renal cell carcinoma; UBC, urothelial bladder cancer; ORR, objective response rate; PDL1, programmed cell death ligand-1; IHC, immunohistochemistry.
Pharmacodynamic biomarkers
Consistent with expected systemic modulation of IDO1, navoximod dosing decreased plasma Kyn relative to Cycle 1 Day 1 pre-dose levels. The mean change from the pre-dose baseline was decreased at all post-dose timepoints beyond 1 hour for patients receiving at least 200 mg navoximod dose (Figure 4A). Similar maximal decreases in Kyn were observed after multiple days of navoximod dosing (Figure 4B). No statistically significant differences in the level of Kyn suppression were observed between responders vs non-responders (Supplemental Figure 1)
Figure 4.
(A) Mean change in plasma Kyn at Cycle 1 Day 1 following a single oral dose of navoximod relative to start of treatment levels. Ribbons represent 95% confidence intervals and dashed horizontal lines represent no change from baseline. (B) Mean change in plasma Kyn at Cycle 1 Day 8 following a single oral dose of navoximod relative to start of treatment levels. Ribbons represent 95% confidence intervals and dashed horizontal lines represent no change from baseline. (C) Serial tumor biopsy evaluation of IDO1, PD-L1, TIL, and CD8. Mean changes in percent positivity and 95% confidence intervals are indicated in each case.
An evaluation of selected biomarkers was carried out in serial tumor biopsies from dose escalation and dose expansion patients that consented to pre-treatment and on-treatment biopsies (Figure 4C). There was upregulation of IDO1 expression in tumor cells following treatment with the combination of navoximod and atezolizumab, although this did not appear to be dose-dependent. An increase in PD-L1 was also observed in some patients. No significant upregulation of IDO1 or PD-L1 in immune cells was observed. No significant intratumoral increases in CD8 or tumor infiltrating leukocytes (TIL) was observed.
Discussion
This Phase 1b study in advanced solid tumors explored the safety, tolerability, PK, and PD of navoximod in combination with atezolizumab. Overall, the combination of atezolizumab and navoximod was generally well-tolerated at the doses explored in this study. No MTD was defined and no apparent dose-response relationship for immune related adverse events was noted over the dose range explored. The potentially immune mediated clinically significant adverse events reported (e.g., hepatitis, pneumonitis, sepsis syndrome) are consistent with the well-established safety profile of atezolizumab and other PD-1/PD-L1 inhibitors.
Rash was observed overall in around 20% of patients and was reported at all doses. It was predominantly Grade 1– 2 in severity, and although rash was the most commonly occurring treatment related Grade 3 AE, only 6 (4%) patients discontinued treatment due to rash, and thus rash was generally manageable. Rash has been reported with other IDO inhibitors (Gangadhar et al. 2015) and may be a class effect of these agents or possibly a combination effect with contributions from both drugs.
Hepatic adverse events had been reported in a single agent study of navoximod (Nayak et al. 2018), and thus inclusion of acetaminophen restrictions (<1000 mg/day on study) were placed for enrolled patients due to the potential risk of elevated LFTs. However, no apparent dose related trend was noted in this study. Hepatic adverse events were commonly confounded by the presence of malignant hepatic infiltration.
The observation of pink colored urine (chromaturia) without associated clinical sequalae in up to 20% of patients remains unexplained despite screening for navoximod metabolites that may be chromogenic, or pathological causes such as hematuria or porphyrins. Chromaturia was documented at greater frequency at higher doses of navoximod and in Asian patients. This finding has not been reported with other IDO inhibitors.
PK and PD analysis revealed that at the evaluated dose levels, navoximod demonstrates a dose-proportional and linear PK profile, and plasma Kyn generally decreased with increasing doses of navoximod. The kinetics of Kyn depletion are consistent with the half-life of the molecule, and generally deeper and more sustained at higher doses, whether after a single oral dose or after multiple doses of navoximod.
In serial tumor biopsies, upregulation of tumor cell IDO1 and PD-L1 expression was observed. Notably, an increase in tumor IDO1 expression was also observed in a neoadjuvant ovarian cancer study following treatment with the IDO1 inhibitor epacadostat (Odunsi et al. 2018). A similarly pronounced upregulation of IDO1 and PD-L1 in immune cells was not observed in this phase 1b study. The observation that neither TIL or CD8 increased post-treatment indicates that the induction of IDO1 and PD-L1 in tumor cells is more likely due to increased interferon gamma production in the tumor microenvironment, rather than to increased immune cell infiltration.
Activity was observed at all dose levels evaluated in this study, but is challenging to interpret in the setting of combination with atezolizumab, which has established single-agent activity in tumor types selected for dose expansion. Although interpretation is limited by small numbers and the single-arm design, the overall response rates in the CIT naïve indication-specific cohorts (n=75), regardless of PD-L1 or IDO1 expression status, are not meaningfully distinct from that expected for atezolizumab alone. For example, in CIT-naïve NSCLC patients previously treated with platinum doublet chemotherapy, the ORR with the combination of navoximod and atezolizumab observed in this study (n=26 patients) was 8% compared to the ORR of 15% observed with atezolizumab monotherapy in the Phase 3 OAK study (Rittmeyer et al. 2016). In light of the limited evidence of clinical activity and lack of robust tumoral PD, the sponsor stopped enrollment in the study and discontinued development of navoximod as a combination partner to atezolizumab.
Subsequent to the analysis of this Phase 1b study, the primary results of the randomized double-blinded Phase 3 ECHO-301 study evaluating epacadostat in combination with pembrolizumab compared to pembrolizumab monotherapy in patients with melanoma have been reported. Despite encouraging Phase 1b results across multiple tumor types supporting this combination, the addition of epacadostat to pembrolizumab was not associated with greater clinical benefit: OS HR 1.13, mPFS of 4.7 vs. 4.9 mo. [HR 1.0], and ORR of 34% vs. 32% (Long et al. 2018), and the trial was halted. Moreover, two Phase III clinical trials testing combinations of nivolumab with BMS-986205, a small molecule that inhibits IDO via a distinct mode of binding than epacadostat and navoximod with greater in vitro potency (Siu et al. 2017), were also halted recently (NCT03417037 and NCT03386838), presumably in response to the negative ECHO-301 results. These results illustrate the challenge of interpreting preliminary findings in small, highly selected Phase 1b expansion cohorts and advancing to pivotal trials without randomized Phase 2 data as well as the value of rigorous integrated analyses of safety, PK, PD, and efficacy data to make development decisions.
To date, proof of concept for adding IDO inhibition to anti-PD-1/PD-L1 to improve clinical benefit has not been achieved. Nevertheless, further interrogation of this pathway may be warranted. Concurrent inhibition of both IDO and TDO2 may be required to relieve kyn-mediated immunosuppression in the TME and drive clinical efficacy, as TDO2 catalyzes the same reaction as IDO, resulting in the production of kyn. In addition, careful patient selection (i.e., patients with positive IDO tumors) is likely to be critical for the success of any future development of IDO inhibitors in combination with anti-PD1/PD-L1 therapy (Dill et al. 2018; Mills et al. 2018).
Supplementary Material
Statement of Translational Relevance.
Preclinical evidence suggests that combining navoximod, an IDO1 inhibitor, with anti-PD-L1 may improve the clinical activity of immune checkpoint blockade due to IDO’s role in immune suppression. This Phase 1 trial is the first study in which the combination of navoximod with atezolizumab was administered to patients with advanced cancer. The combination safety profile appeared tolerable at the navoximod doses administered, which resulted in dose-dependent decreases in plasma Kyn consistent with systemic modulation of IDO1. However, similar to recent data from other trials combining IDO pathway inhibition with PD-L1/PD-1 inhibition (e.g., ECHO-301), the clinical activity observed did not provide compelling evidence of improvement over single agent therapy.
Acknowledgements
The authors wish many thanks to all of the patients and the investigators who participated in this study. We thank the following contributors: Elizabeth Grant for statistical programming analysis support. Writing assistance provided by Genentech, Inc.
Footnotes
ClinicalTrials.gov identifier: NCT02471846
Clinical Cancer Research
http://clincancerres.aacrjournals.org/site/misc/journal_ifora.xhtml
Publisher's Disclaimer: Disclaimer
Publisher's Disclaimer: The authors take full responsibility for the design of the study, the collection of the data, the analysis and interpretation of the data, the decision to submit the article for publication, and the writing of the article.
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