Seeking Answers for Pancreatic Treatment Beyond FOLFIRINOX

Davendra P.S. Sohal, MD, MPH

Davendra P.S. Sohal, MD, MPH

The FOLFIRINOX regimen (folinic acid, fluorouracil, irinotecan, and oxaliplatin) remains the treatment of choice for patients with pancreatic cancer even as clinical trials exploring potential therapies, including CD40 and CPI-613, offer the possibility of new options for a notoriously difficult-to-treat disease, Davendra P.S. Sohal, MD, MPH, told an audience at the 2019 Gastrointestinal Oncology Conference.

Sohal, an assistant professor, director of experimental therapeutics, and clinic medical director at the University of Cincinnati, said FOLFIRINOX is the easy answer for every patient with pancreatic cancer in the adjuvant, neoadjuvant, and metastatic settings. The regimen is effective, according to the results of a phase III trial published inTheNew England Journal of Medicine(NEJM) in 2018 from 493 patients with resected pancreatic ductal adenocarcinoma.¹The trial showed that a modified FOLFIRINOX regimen induced a median overall survival (OS) of 54.4 versus 35.0 months with gemcitabine (HR, 0.64; 95% CI, 0.48-0.86;P= .003). However, only 10% to 20% of patients with pancreatic cancer survive longer than 5 years.¹

Furthermore, the regimen is associated with high levels of toxicity. TheNEJMstudy showed that 75.9% of patients randomized to receive FOLFIRNOX experienced grade 3/4 adverse events compared with 52.9% in the gemcitabine arm.

At present, physicians have limited options beyond FOLFIRINOX. PARP inhibition targeting homologous recombination repair—deficient tumors showed some promise in the phase III POLO trial. Findings published in July 2019 showed that treatment with olaparib (Lynparza) improved progression-free survival (PFS) compared with placebo (7.4 vs 3.8 months; HR, 0.53; 95% CI, 0.35-0.82;P= .004) for patients with a germlineBRCA1/2mutation and metastatic pancreatic cancer who did not progress during first-line platinum-based chemotherapy. However, as of the interim analysis, olaparib did not improve OS (18.9 vs 18.1 months; HR, 0.91; 95% CI, 0.56-1.46;P= .68). Additionally, Sohal said only approximately 7.5% of patients with pancreatic cancer harborBRCA1/2mutations.²

Initial experiments with immunotherapy with or without chemotherapy did not produce positive results. Findings with gemcitabine/nab-paclitaxel (Abraxane) plus nivolumab (Opdivo) in the first line and durvalumab (Imfinzi) and tremelimumab in the second line proved to be disappointing with low response rates.^3,4

“This approach, which has worked well in other cancers—PD-1 and CTLA-4 combination therapy, doesn't really pan out in pancreatic cancer using durvalumab/tremelimumab,” Sohal said.

However, CD40 agonism has demonstrated efficacy in small studies. The protein is broadly expressed and leads to priming of antigen-presenting cells, especially dendritic cells and B cells, Sohal said.

“It basically revs up the immune system,” he added. “It is ideally given on day 3 after chemotherapy or even radiation on day 1, which leads to tumor cell [death and] antigen release.”

Mark H. O’Hara, MD, assistant professor of medicine at the Perelman School of Medicine at the University of Pennsylvania, presented results from a multicenter, phase Ib/II clinical trial evaluating the combination of APX005M, a monoclonal antibody targeting CD40, with nivolumab and gemcitabine/nab-paclitaxel at the 2019 American Association for Cancer Research Annual Meeting.

Patients with treatment-naïve pancreatic adenocarcinoma were enrolled to 2 cohorts of nivolumab and gemcitabine/nab-paclitaxel plus 2 different dose levels of APX005M or 2 cohorts of chemotherapy without nivolumab plus 2 different dose levels of APX005M. At a median follow-up of 32.2 weeks, 13 (54%) patients achieved a partial response and 9 (38%) had stable disease across the 4 cohorts. Only 1 (4%) patient had progressive disease.⁵

“This is pretty encouraging,” Sohal said. “This is an avenue that should be explored. This approach seems to get the immune system activated against the tumor.”

He added that the O’Hara findings did not include a chemotherapy control group. Sohal said APX005M needs to be evaluated in a randomized controlled trial to determine how much CD40 adds to chemotherapy and if it is necessary to include PD-1/CTLA-4 checkpoint inhibitors to maintain that effect or if CD40 agents can be used as monotherapy.

Investigators are also exploring ways to interfere with the metabolism of a tumor cell and CPI-613 has emerged as a promising novel agent. CPI-613 selectively targets the mitochondrial energy metabolism in tumor cells and alters mitochondrial enzyme activities. The result is apoptosis, necrosis, and autophagy of tumor cells.

“It gums up the cellular metabolic machinery and leads to an accumulation of toxins and cell death,” Sohal said.

In findings from a phase I dose-escalation trial of 20 adults with newly diagnosed metastatic pancreatic adenocarcinoma, CPI-613 plus modified FOLFIRINOX induced a response rate of 61% with a median PFS of 11.5 months. The median OS was not reached.⁶

CPI-613 with or without modified FOLFIRINOX is currently being assessed in the ongoing phase III PANC003 (NCT03504423) trial. Investigators hope to recruit 500 adults with metastatic disease. The estimated primary completion date is October 2021.

Sohal calledTP53avoidance the "holy grail" of pancreatic cancer treatment and said investigators are exploring epigenetic differentiation therapy withdecitabine(Dacogen). The treatment essentially avoids the intrinsic mitochondrial apoptotic pathway that is dependent on p53. That leads to epigenetic differentiation, meaning that cancer stem cells differentiate and stop dividing.

Investigators determined that epigenetic differentiation with decitabine was feasible in a small trial of 13 patients with pancreatic cancer who had progressed on prior therapy. However, they did not observe any responses and only 1 patient had stable disease. Sohal said they determined that 5-azacitidine (Vidaza) is necessary for enzymatic stability in the drug.

“Just like PD-1 and CTLA-4, in a way, you need both these drugs,” he said. “We are launching a clinical trial to study this TP53 avoidance strategy as well.”

References

1. Conroy T, Hammel P, Hebbar M, et al; Canadian Cancer Trials Group and the Unicancer-GI—PRODIGE Group. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer.N Engl J Med. 2018;379:2395-2406. doi: 10.1056/NEJMoa1809775.
2. Golan T, Hammel P, Reni M, et al. Maintenance olaparib for germlineBRCA-mutated metastatic pancreatic cancer.N Engl J Med. 2019;381:317-327. doi: 10.1056/NEJMoa1903387.
3. Wainburg ZA, Hochster HS, Kim EJH, et al. Phase I study of nivolumab (Nivo) + nab-paclitaxel (nab-P) + gemcitabine (Gem) in advanced pancreatic cancer (APC).J Clin Oncol. 2019;37(suppl 4; abstr 298).
4. O’Reilly EM, Oh DY, Dhani N, et al. Durvalumab With or Without Tremelimumab for Patients With Metastatic Pancreatic Ductal Adenocarcinoma: a Phase 2 Randomized Clinical Trial.JAMA Oncol. 2019;5(10):1431-1438. doi: 10.1001/jamaoncol.2019.1588.
5. O'Hara MA, O'Reilly EM, Rosemarie M, et al. A Phase Ib study of CD40 agonistic monoclonal antibody APX005M together with gemcitabine (Gem) and nab-paclitaxel (NP) with or without nivolumab (Nivo) in untreated metastatic ductal pancreatic adenocarcinoma (PDAC) patients. Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. Abstract CT004.
6. Alistar A, Morris BB, Desnoyer R, et al. Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial.Lancet Oncol.2017;8(6):770-778. doi: 10.1016/S1470-2045(17)30314-5.