Devimistat Plus Modified FFX Misses the Mark in Metastatic Pancreatic Adenocarcinoma

Philip A. Philip, MD, PhD, FRCP

The combination of devimistat (CPI-613) and modified fluorouracil, oxaliplatin, irinotecan, and leucovorin (mFFX) did not significantly improve short- or long-term outcomes over standard-dose FFX in patients with metastatic pancreatic adenocarcinoma, according to data from the phase 3 AVENGER 500 trial (NCT03504423).^1,2

The full trial findings, which are now published in the Journal of Clinical Oncology, showed that in the intention-to-treat (ITT) population, the median overall survival (OS) was 11.10 months (95% CI, 10.22-12.94) with devimistat plus mFFX (n = 266) compared with 11.73 months (95% CI, 10.12-13.24) with FFX (n = 262), missing the primary end point of the trial (P = .6555). The median follow-up in these respective arms was 18.7 months and 19.2 months.

The respective objective response rates (ORRs) in these arms were 39.1% (95% CI, 33.2%-45.0%) and 34.4% (95% CI, 28.6%-40.1%; OR unadjusted for stratification factors, 1.23; 95% CI, 0.86-1.75). After adjustment for stratification factors, no difference in OR was reported between the treatment arms (OR, 1.23; 95% CI, 0.85-1.76). No difference was observed between the arms with regard to median duration of response either.

At a median follow-up of 10.9 months in the devimistat/mFFX arm and 5.9 months in the FFX arm, the median progression-free survival (PFS) was 7.82 months (95% CI, 6.97-10.91) and 7.98 months (95% CI, 7.23-11.14) in the respective arms (HR, 0.99; 95% CI, 0.76-1.29; P = .94).

“In conclusion, there was no benefit with the addition of devimistat to mFFX in patients with metastatic pancreatic cancer,” Philip A. Philip, MD, PhD, FRCP, of Henry Ford Health, and colleagues wrote in the paper. “The targeting of the altered metabolism of cancer cells has long been thought to be a rational and an attractive hypothetical approach in this highly unmet disease but targeting the metabolism in patients with pancreatic cancer has not been crowned with success. There is an urgent need to develop better strategies that can be explored preclinically, especially combinations that would mitigate the metabolic adaptations of cancer cell resistance to a single enzyme/ pathway blockade.”

The prospective, multicenter, open-label, randomized, phase 3 AVENGER 500 study enrolled patients with histologically or cytologically confirmed stage IV pancreatic cancer who had not previously received systemic therapy. They were required to be between the ages of 18 and 75 years, have an ECOG performance status of 0 or 1, and measurable disease by RECIST 1.1 criteria.

Exclusion criteria included endocrine or acinar pancreatic carcinoma, central nervous system metastases, significant abdominal ascites, a history of myocardial infarction within 3 months prior to registration, or a notable prolonged QT or QTc interval at baseline.

Those in the investigative arm were administered 500 mg/m2 of intravenous (IV) devimistat on days 1 and 3 at 4 mL/min concurrently with dextrose 5% in water at 125 mL/h via a central venous catheter; this was followed by 65 mg/m2 of IV oxaliplatin administered over 2 hours, 400 mg/m2 of IV folinic acid over 1.5 hours given concurrently with 140 mg/m2 of irinotecan and fluorouracil at 400 mg/m2 IV bolus followed by a 42- to 48-hour infusion at 2400 mg.

Those in the control arm were given the full dose of FFX, which comprised 85 mg/m2 of oxaliplatin over 2 hours, 400 mg/m2 of folinic acid over 1.5 hours given concurrently with 180 mg/m2 of irinotecan, 400 mg/m2 of fluorouracil, followed by a 42- to 48-hour infusion at 2400 mg/m2.

In addition to the primary end point of OS, secondary end points comprised PFS, ORR, DOR, and safety.

In the total population, the median age was 63 years with 64.2% of patients aged 60 years or older. Moreover, 59.5% of patients were male and 52.3% had an ECOG performance status of 1. Primary tumor locations included head of pancreas (43.2%), tail of pancreas (28.8%), and body of pancreas (28.0%). Additionally, 44.5% of patients had elevated CA19-9 of at least 59 U/mL x the upper limit of normal (ULN), 34.3% had elevated CA19-9 below 59 x ULN, and 14.8% had normal CA19-9.

Of the 266 patients randomly assigned to the devimistat/mFFX arm, 259 received treatment. At the time of data cutoff, 23 were still receiving the regimen and 236 and discontinued. The most common reason for discontinuation was disease progression (n = 145), followed by toxicities (n = 40), patient withdrawal (n = 20), physician decision (n = 14), death (n = 12), or other reasons (n = 5). Of the 262 patients assigned to the control arm, 235 received treatment and 16 were still receiving treatment. A total of 219 patients discontinued treatment due to disease progression (n = 101), patient withdrawal (n = 47), adverse effects (AEs; n = 43), physician decision (n = 16), and other (n = 8).

Data from unplanned subgroup analyses did not reveal any statistically significant differences in OS benefit with the regimens spanning age (<55 years: HR, 1.362; 55-70 years: HR, 0.935; >70 years: HR, 0.934) sex (female: HR, 0.859; male: HR, 1.107), geographic region (Asia or Pacific: HR, 0.961; Europe: HR, 1.103; North America: HR, 0.987), race (Asian: HR, 1.118; Black or African American: HR, 1.273; White: HR, 1.001; American Indian: HR, 0.000), ethnicity (Hispanic or Latino: HR, 1.420; Not Hispanic or Latino, HR: 0.986), or albumin result (Low: HR, 1.097; Normal/high; HR, 0.970).

Regarding safety, 99.6% of those in the devimistat arm experienced a treatment-emergent AE (TEAE) vs 98.7% of those in the control arm. Serious TEAEs occurred in 54.1% and 56.6% of patients, respectively. A total of 73.4% of patients in the investigative arm experienced TEAEs associated with devimistat. Grade 3 or higher devimistat-related TEAEs occurred in 45.6% of patients. Serious TEAEs associated with devimistat occurred in 13.9% of patients.

TEAEs resulting in dose modifications, interruptions, or discontinuations of devimistat plus mFFX occurred in 75.7% of patients; 77.9% of patients required modifications, interruptions, or discontinuation of FFX. TEAEs led to change in concomitant therapy for 88.0% and 88.1% of those in the devimistat and control arms, respectively. TEAEs resulted in death for 8.9% of those in the devimistat arm and 3.4% of those in the control arm.

The most common grade 3 or higher TEAEs to occur in the devimistat/mFFX and FFX arms, respectively, were neutropenia (29.0%; 34.5%), diarrhea (11.2%; 19.6%), hypokalemia (13.1%; 14.9%), anemia (13.9%; 13.6%), decreased platelet count (11.6%; 13.6%), and fatigue (10.8%; 11.5%).

“Although not the primary study intent, this dataset provides support that modified dosing of FFX is an accepted and arguably preferred way of administering this cytotoxic regimen,” Eileen M. O’Reilly, MD, of Memorial Sloan Kettering in New York, New York, and associate editor of JCO, wrote. “Further, the study represents one of the first phase III trials building, albeit unsuccessfully, on FFX.”

Reference

1. Philip PA, Sahai V, Bahary N, et al. Devimistat (CPI-613) with modified fluorouracil, oxaliplatin, irinotecan, and leucovorin (FFX) versus FFX for patients with metastatic adenocarcinoma of the pancreas: the phase III AVENGER 500 study. J Clin Oncol. Published inline August 1, 2024. doi:10.1200/JCO23.02659