Novel Combination May Break Outcomes Stalemate in Pancreatic Cancer

Philip A. Philip, MD, PhD

Therapeutic breakthroughs for patients with metastatic pancreatic cancer have eluded investigators for decades, with chemotherapeutic combination strategies serving as the insurmountable standard of care. Investigators are seeking to overcome the stagnation and fill an unmet need for improved survival benefit in this patient population with devimistat, a novel agent designed to target the mitochondrial tricarboxylic acid (TCA) cycle in the phase 3 AVENGER 500 trial (NCT03504423).¹

“[It has been] 2 decades since the first drug [for patients with pancreatic cancer] was approved by the FDA—gemcitabine— and since then our progress in pancreatic cancer has been really very unsatisfactory,” said Philip A. Philip, MD, PhD, in an interview with OncologyLive^®. “After 2 decades or so, we have only 2 regimens that we use: one is the gemcitabine and Abraxane [nab-paclitaxel] and the other one is a triplet called FOLFIRINOX [leucovorin, 5-fluorouracil, irinotecan hydrochloride, and oxaliplatin].” Philip is a professor of hematology-oncology at Wayne State University School of Medicine and leader of the Gastrointestinal and Neuroendocrine Oncology Multidisciplinary Team at Barbara Ann Karmanos Cancer Institute in Detroit, Michigan.

Building on the Standard of Care

FOLFIRINOX as well as the combination of gemcitabine and nab-paclitaxel are the 2 preferred regimens for patients with metastatic pancreatic cancer. However, survival benefits have been limited to those with good performance status, including Eastern Cooperative Oncology Group performance status of 0 to 1, good biliary drainage, and adequate nutritional intake.²

FOLFIRINOX bested single-agent gemcitabine and demonstrated its efficacy in data from the phase 3 PRODIGE trial (NCT00112658). At a median follow-up of 26.6 months, the median overall survival (OS) was 11.1 months (95% CI, 9.0-13.1) in the FOLFIRINOX arm vs 6.8 months (95% CI, 5.5-7.6) in the gemcitabine arm (HR, 0.57; 95% CI, 0.45-0.73; P < .001).3 Further, OS rates were 75.9%, 48.4%, and 18.6%, at 6, 12, and 18 months, respectively, in the FOLFIRINOX arm compared with 57.6%, 20.6%, and 6.0% in the gemcitabine arm.

The median progression-free survival (PFS) for patients treated with FOLFIRINOX was nearly double that of those who received gemcitabine at 6.4 months (95% CI, 5.5-7.2) and 3.3 months (95% CI, 2.2-3.6), respectively (HR, 0.47; 95% CI, 0.37-0.59; P < .001).³

Additionally, the toxicities associated with FOLFIRINOX are of concern as investigators look to add therapeutics that have their own effects. For example, safety analysis from PRODIGE showed incidence of grade 3/4 neutropenia in 45.7% of patients treated with FOLFIRINOX (n = 171) vs 21% in those treated with gemcitabine monotherapy (n = 171; P < .001).³ Despite the higher incidence of AEs, the regimen out performed gemcitabine alone in regard to quality of life. At 6-month follow-up, 31% of patients in the FOLFIRINOX arm had definitive decrease in Global Health Status and Quality of Life scale scores compared with 66% in the gemcitabine arm (HR, 0.47; 95% CI, 0.300.70; P < .001).

Improvements in survival data compared with less toxic regimens have left the chemotherapy combination uncontested in its spot as the standard for those with good performance, leaving investigators to set their sights on less toxic combination regimens to move the needle.

Devimistat is an intravenous small molecular dual inhibitor of pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, 2 of the major reregulated control points that input carbon into the TCA cycle of cancer cells.^4,5

In the phase 1 dose-escalation study (NCT01835041), 18 patients with pancreatic cancer received the agent in combination with a modified FOLFIRINOX regimen at the maximum-tolerated dose. Results showed that 61% of patients had an objective response to the treatment, the median OS was 19.9 months, and the median PFS was 9.9 months. Three patients had a reported complete response to treatment (17%).

Of note, safety data for the combination regimen demonstrated that it was well tolerated, with expected adverse effects (AEs) including thrombocytopenia, anemia, and lymphopenia. For the 18 patients evaluated at the maximum-tolerated dose, the most common grade 3/4 AEs were hypokalemia (33%), diarrhea (28%), and abdominal pain (22%). Seventeen patients experienced sensorial neuropathy (94%), which investigators reported was managed with dose de-escalation or discontinuation. No patients experienced grade 5 AEs.

“The metabolism of the cancer cell is not the same as [it is in] the normal cell, so we’re trying to really exploit that differential between the normal cell and the cancer cell,” Philip said. “Devimistat [inhibits] a couple of enzymes in the TCA cycle, and these are enzymes critical to the way that the cancer cells generate energy.” Philip added that the mechanism of action of devimistat also allows it to affect the metabolism of the cancer cells without causing much harm to normal cells.

Leveraging the data collected in the phase 1 study, investigators of the AVENGER 500 trial will randomize individuals 1:1 to evaluate the efficacy of FOLFIRINOX compared with the combination of devimistat plus a modified FOLFIRINOX regimen (FIGURE⁶). Those randomized to the experimental arm will receive devimistat 500 mg/m2 on days 1 and 3 of a 14-day cycle; the modified FOLFIRINOX regimen comprises the standard dose and schedule of 5-fluorouracil and leucovorin and uses reduced doses of oxaliplatin (65 mg/m²) and irinotecan (140 mg/m²). The control arm uses the standard regimen: leucovorin (400 mg/m2), 5-fluorouracil (400 mg/m² as a bolus followed by 2400 mg/m² as a 46-hour infusion), oxaliplatin (85 mg/m²), and irinotecan (180 mg/m²). The trial has met its target enrollment of 500 patients.⁷

“One thing which was surprising to me as an investigator and surprising to everyone who was involved in the trial is that despite COVID-19 hitting in the spring of 2020, the trial continued to accrue very fast,” Philip said. “It just gives you the idea that individuals are desperate to find something, and patients [with pancreatic cancer] are desperate to be on a clinical trial because that is a potential benefit for them.”

Another result of the fast accrual was the opportunity to adjust the trial design to use OS as the primary end point rather than PFS. The change was made in June 2021.⁶

“With the number of patients who were accrued, we will have enough events go into [waiting for the data on] overall survival. Ultimately, overall survival is what matters to patients and what matters also to the FDA in the long run, in terms of having a drug approved,” Philip said. The sponsor of the trial, Raphael Pharmaceuticals, in consultation with statisticians and the study steering committee, has decided to wait for the more meaningful outcome data.

“It was a function of the trial growing very fast. And when that happens, you might as well just wait a bit longer in your analysis and get to the end point that everyone wants to know [about],” Philip added.

In addition to PFS, secondary end points include duration of response and overall response rate.⁴ The treatment phase will consist of a minimum of 12 cycles of therapy in responding patients with acceptable tolerance and include predosing tests, AE assessment, and a radiology scan for the measurement of overall response every 8 weeks. In the follow-up phase, investigators will assess patients every 2 months for OS and PFS until death.⁶

Fulfilling an Unmet Need

In November 2020, devimistat received fast track designation from the FDA.⁷ Data from the AVENGER 500 trial will, hopefully, pave a path forward for the full approval of devimistat.

The agent is also under investigation with the alternative standard-of-care option for patients with metastatic pancreatic cancer, gemcitabine plus nab-paclitaxel. In data from a phase 1 trial (NCT03435289), presented at the 2020 American Society of Clinical Oncology Virtual Scientific Program, the combination elicited an objective response rate of 50% among 20 evaluable patients. Specifically, the addition of devimistat elicited a 5% complete response rate and a 45% partial response rate. Forty percent of patients had stable disease and the remaining 10% experienced disease progression.⁸

“There is a high unmet need [for these patients],” Philip said. “Pancreatic cancer really falls behind almost all other cancers in terms of effective drug therapies because most patients with pancreatic cancer present with advanced disease requiring systemic treatment.

“Even the minority, less than 20%, who may present with localized disease that can be removed by surgery, still require chemotherapy to clean up the micrometastatic disease, which most of them have. Even then, unfortunately, after having radical surgery and additional chemotherapy, patients will ultimately succumb to their disease because of recurrence. [This patient population] requires effective systemic treatment that we do not currently have.”

“I’m looking forward to seeing how the results shake out because it would be nice to see some improvements for these patients,” Philip noted.

References

1. CPI-613 (devimistat). Rafael Pharmaceuticals, Inc. Accessed June 20, 2021. https://rafaelpharma.com/research-and-development/cpi-613-drug 
2. Philip PA, Buyse ME, Alistar AT, et al. Avenger 500, a phase III open-label randomized trial of the combination of CPI-613 with modified FOLFIRINOX (mFFX) versus FOLFIRINOX (FFX) in patients with metastatic adenocarcinoma of the pancreas. J Clin Oncol. 2019;37(suppl 4):TPS479. doi:10.1200/JCO.2019.37.4_suppl.TPS479
3. Gao L, Xu Z, Huang Z, et al. CPI-613 rewires lipid metabolism to enhance pancreatic cancer apoptosis via the AMPK-ACC signaling. J Exp Clin Cancer Res. 2020;39(1):73. doi:10.1186/s13046-020-01579-x
4. Study evaluating efficacy and safety of FFX versus combination of CPI-613 with mFFX in patients with metastatic adenocarcinoma of the pancreas. ClinicalTrials.gov. Updated June 9, 2021. Accessed June 21, 2021. https://clinicaltrials.gov/ct2/show/NCT03504423 
5. Rafael Pharmaceuticals receives FDA fast track designation for CPI-613 (devimistat) for the treatment of pancreatic cancer. News release. Rafael Pharmaceuticals. November 10, 2020. Accessed June 21, 2020. https://bit.ly/3eIrG8H 
6. Alistar AT, Morris B, Harrison L, et al. A single-arm, open-label, phase I study of CPI-613 (devimistat) in combination with gemcitabine and nab-paclitaxel for patients with locally advanced or metastatic pancreatic adenocarcinoma. J Clin Oncol. 2020;38(suppl 15):4635. doi:10.1200/JCO.2020.38.15_suppl.4635