Novel Therapeutics, Dosing Strategies Offer Hope in Metastatic Pancreatic Cancer

Shubham Pant, MD

Given the poor prognosis of pancreatic cancer and the steady stream of negative phase III trials, clinicians are facing an uphill battle in the treatment of this patient population.

“There is nothing known as early pancreatic cancer; it’s truly a metastatic disease with a dire prognosis in which as many patients die of [their cancer] as those who get diagnosed every year,” said Shubham Pant, MD, in a presentation during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Cancers.

In the presentation, Pant, associate medical director of the Clinical & Translational Research Center, associate professor, Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center, discussed established and investigational frontline approaches as well as maintenance strategies designed to potentially improve the prognosis of patients with advanced disease.

In terms of frontline therapy, clinicians have a choice between FOLFIRINOX or the combination of gemcitabine and nab-paclitaxel (Abraxane), explained Pant.

In the PRODIGE 4/ACCORD 11 trial, 342 patients with an ECOG performance score ≤1 were randomized to receive FOLFIRINOX or gemcitabine. The median overall survival (OS) was 11.1 months in the FOLFIRINOX arm and 6.8 months in the gemcitabine arm, reflecting a 43% reduction in the risk of death with FOLFIRINOX (HR, 0.57; 95% CI, 0.45-0.73; P <.001).¹ The median progression-free survival (PFS) also favored FOLFIRINOX compared with gemcitabine at 6.4 months versus 3.3 months, respectively (HR, 0.47; 95% CI, 0.37-0.59; P <.001).

Regarding safety, FOLFIRINOX was associated with a higher rate of grade ≥3 toxicities than gemcitabine, the most common being fatigue, neutropenia, and sensory neuropathy. For that reason, Pant said the regimen may be more suitable for a younger patient with a good performance status and organ function.

However, a retrospective analysis conducted at The University of Texas MD Anderson Cancer Center suggests that patients ≥75 years of age with unresectable disease do not necessarily have to forego the regimen, explained Pant. In the study, patients with a median age of 76 years (range, 75-84) were dose reduced and displayed similar rates of median OS and grade ≥3 toxicity as in the initial phase III MPACT study, at 11.6 months (95% CI, 6.1-15.7) and 45.8%, respectively.²

“You can give FOLFIRINOX to patients older than 75 years old, but you have to dose adjust,” said Pant.

Two years later, investigators noted the superiority of gemcitabine in combination with nab-paclitaxel versus gemcitabine alone in an international phase III trial.³ In the study, 861 patients with a Karnofsky performance score (KPS) ≥70 were randomized to 125 mg/m² of nab-paclitaxel and 1000 mg/m² of gemcitabine on days 1, 8, and 15 of every 4-week cycle or gemcitabine alone. The rates of median OS were 8.5 months and 6.7 months in the combination and control arms, respectively, resulting in a 1-year survival rate of 35% in the combination arm compared with 22% in the control arm. The combination also resulted in a 1.8-month extension in median PFS (HR, 0.69; 95% CI, 0.58-0.82; P <.001).

Notably, the combination showed a consistent benefit across all prespecified subgroups, including patients with poorer performance status (KPS ≤80), liver metastases, ≥3 sites of metastatic disease, and metastatic disease at diagnosis.

Dose modifications can also be made in clinical practice, although this was not formally examined in the trial, said Pant. In practice, the combination can be given biweekly or as a weekly regimen on: days 1, 8, and 15 every 28 days in which nab-paclitaxel is given at 100 mg/m², days 1 and 8 every 21 days with no dose modification, or days 1 and 8 every 21 days in which nab-paclitaxel is given at 100 mg/m².

“Patients will require dose modification whether you give gemcitabine/nab-paclitaxel or FOLFIRNOX,” said Pant.

Subsequently, an oxaliplatin stop-and-go strategy was compared with standard chemotherapy in patients with metastatic disease with no prior exposure to chemotherapy or radiotherapy.⁴ Patients were randomized to 1 of 3 arms: FOLFIRINOX every 2 weeks for a maximum of 12 cycles (arm A); FOLFIRNOX for 4 months for 8 cycles, followed by LV5FU2 (leucovorin 85 mg/m², 5-fluorouracil [5-FU] bolus 400 mg/m², 5-FU infusion 2400 mg/m²) as maintenance until progression (arm B; stop-and-go); or sequential therapy with FOLFIRI.3 and gemcitabine every 2 months (arm C).

Six-month PFS served as the primary endpoint of the study in the modified intent-to-treat population (mITT). Across Arms A, B, and C, these rates were 47.1%, 44.0%, and 34.1%, respectively. Arm C also resulted in inferior rates of median PFS and OS, although the median PFS among the ITT population was comparable between arms A and B, at 6.3 months (95% CI, 5.3-7.6) and 5.7 months (95% CI, 5.3-7.5), respectively. Additionally, the median OS was 10.1 months (95% CI, 8.5-12.2) and 11.0 months (95% CI, 8.7-13.1) in arms A and B, respectively.

Grade 3/4 adverse events were similar between arms A and B, although the rate of sensory neuropathy was higher in arm B at 18.7% than arm A at 10.2%, due to the reintroduction of FOLFIRNOX and markedly longer exposure to oxaliplatin.

“Maintenance LV5FU2 after 4 months of induction chemotherapy with FOLFIRNOX seems to be feasible and effective,” said Pant.

With regard to emerging agents in the metastatic setting, Pant explained that pegvorhyaluronidase alfa (PEGPH20) has shown a clinical benefit as frontline therapy when added to gemcitabine and nab-paclitaxel. In the phase II HALO-109-202 trial, the triplet regimen reduced the risk of disease progression or death by 27% (HR, 0.73) in all comers and 49% (HR, 0.51) in those with hyaluronan (HA)-high disease.⁵ The regimen is now being tested in an ongoing phase III trial (NCT01839487) to confirm the benefit that has been observed to date.

Napabucasin, an oral STAT3 inhibitor, has also been put forward as a potential agent for cancer stem cell (CSC) inhibition, explained Pant. By directly binding to STAT3—a key regulator of cancer stemness—napabucasin may be able to block CSC self-renewal and kill CSC and cancer cells.

In the ongoing phase III CanStem111P trial (NCT02993731), treatment-naïve patients will be randomized 1:1 to receive either napabucasin twice daily plus 125 mg/m² of nab-paclitaxel and 1000 mg/m² of gemcitabine every 3 of 4 weeks, or gemcitabine and nab-paclitaxel alone until disease progression or unacceptable toxicity.

Beyond progression on frontline therapy, Pant explained that subsequent treatment can be broken down by performance status and prior therapy, whereby patients with an ECOG score ≤1 who received a gemcitabine-based therapy as frontline therapy can receive nanoliposomal irinotecan plus 5-FU and those with an ECOG score of 2 can receive single-agent fluoropyrimidine. The second-line setting for patients who received FOLFIRINOX is less well-defined, said Pant, although gemcitabine-based therapy is generally recommended.

As more research is done, treatment approaches may become more dependent on specific subgroups of patients, explained Pant, of which the strongest correlative treatment responses have been shown with immunotherapy and microsatellite instability—high tumors, as well as PARP inhibition and DNA-damage response pathways.

“We’re improving treatment options with novel therapeutics,” concluded Pant. “[We’re seeing] a light at the end of the tunnel.”

References

1. Conroy T, Desseigne F, Ychou M, et al; Groupe Tumeurs Digestives of Unicancer, PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817-1825. doi: 10.1056/NEJMoa1011923.
2. Mizrahi J, Rogers J, Hess KR, et al. FOLFIRINOX in pancreatic cancer patients age 75 years or older. J Clin Oncol. 2019;37 (suppl 4, abstr 362). doi: 10.1200/JCO.2019.37.4.
3. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691-1703. doi: 10.1056/NEJMoa1304369.
4. Dahan L, Phelip JM, Le Malicot K, et al. FOLFIRINOX until progression, FOLFIRINOX with maintenance treatment, or sequential treatment with gemcitabine and FOLFIRI.3 for first-line treatment of metastatic pancreatic cancer: a randomized phase II trial (PRODIGE 35-PANOPTIMOX). J Clin Oncol. 2018;36 (suppl 15, abstr 4000). doi: 10.1200/JCO.2018.36.15_suppl.4000.
5. Hingorani S, Zheng L, Bullock AJ, et al. HALO 202: randomized phase II study of PEGPH20 plus nab-paclitaxel/gemcitabine versus nab-paclitaxel/gemcitabine in patients with untreated, metastatic pancreatic ductal adenocarcinoma. J Clin Oncol. 2018;36(4):359-366. doi: 10.1200/JCO.2017.74.9564.