Increased Incidence Drives Novel Approaches Across Pancreatic Cancer Settings

Allen L. Cohn, MD

Pancreatic cancer mortality is on the rise compared with other gastrointestinal malignancies, spurring an abundance of novel treatment approaches to combat the disease.

One such approach is neoadjuvant therapy, said Allen L. Cohn, MD, in a presentation during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Malignancies.

“Years ago, we would never be talking about [neoadjuvant therapy]. We never really thought about it because we never really had any good drugs,” said Cohn, a medical oncologist at Rocky Mountain Cancer Centers.

However, for patients with unresectable locally advanced and borderline resectable disease, neoadjuvant therapy can now be considered as a way to decrease the risk of local recurrence after surgery and delay the risk of distant recurrence. Positive prognostic factors, as illustrated by a recently published study from Mayo Clinic, include a decrease in CA19-9 levels to within normal range, a major pathologic response at the time of resection, and extended duration of chemotherapy, said Cohn. Historical algorithms indicated that patients with resectable disease should proceed to surgery first, but these patients may also qualify for neoadjuvant chemotherapy.

The prevalence of neoadjuvant chemotherapy has risen as a whole, but it has undoubtedly had the biggest impact on patients with borderline resectable disease, added Cohn.

Although adjuvant therapy has been a staple of treatment, modifications to standard regimens have tremendously impacted efficacy, explained Cohn. First reported at the 2018 ASCO Annual Meeting, the phase III PRODIGE 24/CCTG PA.6 trial showed a 42% reduction in the risk of disease progression or death in patients who received modified FOLFIRINOX following an R0 or R1 resection versus gemcitabine alone.¹ However, tolerability remains a concern. Despite the fact that the fluorouracil (FU) bolus was dropped, patients may have a hard time tolerating the regimen for the full 6 months.

“You really want to get started as soon as possible after surgery,” said Cohn.

In the advanced setting, FOLFIRINOX was one of the first regimens to be compared favorably with the then standard gemcitabine monotherapy. The standard shift was based on results from the PRODIGE 4/ACCORD 11 trial, which randomized 342 patients with metastatic disease to receive either FOLIRINOX (n = 171) or gemcitabine (n = 171) for 6 months.

Progression-free survival ([PFS]; HR, 0.47; 95% CI, 0.37-0.59; P <.001) and overall survival ([OS]; HR, 0.57; 95% CI: 0.45-0.73; P <.001) favored FOLFIRINOX over gemcitabine and, as such, FOLFIRINOX should be recommended for patients who are able to tolerate it.²

“It’s like any regimen,” explained Cohn. “As it’s been out, we’ve learned to use it better with modifications, such as holding the 5-FU bolus and cutting the irinotecan from 180 mg/m² to 150 mg/m².”

Subsequently, the combination of gemcitabine and nab-paclitaxel (Abraxane) has become an alternative to FOLFIRINOX based on the results of the phase III MPACT trial,³ which demonstrated a 31% reduction in the risk of progression or death compared with gemcitabine alone in patients with metastatic pancreatic cancer.

Cross-trial comparisons, though never endorsed, do suggest that OS and PFS are longer with FOLFIRINOX than with the combination of gemcitabine and nab-paclitaxel. However, the incidence of fatigue and neutropenia is higher.

An ongoing trial (NCT01839487) comparing the addition of pegvorhyaluronidase alfa (PEGPH20) to the combination of gemcitabine and nab-paclitaxel versus the combination alone may place the triplet above FOLFIRINOX as a frontline choice, added Cohn, especially for patients with hyaluronan-high disease following phase II results of the HALO 202 trial, which indicated a median OS of 11.5 months versus 8.5 months, respectively (HR, 0.96; 95% CI, 0.57-1.61).⁴

With two established regimens in the frontline setting, investigators turned their interest toward second-line therapy. By 2016, the phase III NAPOLI-1 trial5 had accrued 417 gemcitabine-refractory patients to be randomized to the combination of nanoliposomal irinotecan and 5-FU/leucovorin, 5-FU/leucovorin alone, and a safety run-in of nanoliposomal-irinotecan.

Results from the trial indicated a median OS of 6.1 months (95% CI, 4.8-8.9 months) and 4.2 months (95% CI, 3.3-5.3 months) with the combination versus 5-FU/leucovorin, respectively (HR, 0.67; 95% CI, 0.49-0.92; P = .012). The combination also demonstrated a statistically significant improvement in median PFS over 5-FU/leucovorin, at 3.1 months versus 1.5 months, respectively.

“We saw a nice 17% response rate [with the combination], which is something we usually don’t expect to see in a second-line pancreatic trial,” said Cohn.

As such, the combination received regulatory approval in 2015 for use in patients with advanced gemcitabine-refractory disease.

In terms of genetic alterations, physicians should screen for BRCA1/2 mutations, although it is present in approximately 5% of all pancreatic cancers. There are several ongoing phase II/III trials for patients with germline BRCA-mutated metastatic disease, one of which has already demonstrated positive results.

Moreover, recently presented at the 2019 ASCO Annual Meeting were data from the phase III POLO trial, which showed that patients who had not progressed on frontline platinum-based chemotherapy and received maintenance therapy with the PARP inhibitor olaparib (Lynparza) experienced a 7.4-month median PFS compared with 3.8 months in the placebo arm.^6,7

Editor’s Note: This presentation took place prior to the results of the phase III POLO trial presented at the 2019 ASCO Annual Meeting.

References

1. Conroy T, Hammel P, Hebbar M, et al; CCTG and the UNICANCER-GI/PRODIGE Group. Unicancer GI PRODIGE 24/CCTG PA.6 trial: a multicenter international randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine (gem) in patients with resected pancreatic ductal adenocarcinomas. J Clin Oncol. 2018;36(suppl 18, abstr LBA4001). doi: 10.1200/JCO.2018.36.18_suppl.LBA4001.
2. 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.
3. Von Hoff DD, Ervin T, Arena FF, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Eng J Med. 2013;369(18):1691-1703. doi: 10.1056/NEJMoa1304369.
4. Hingorani SR, 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.
5. Chen L-T, Von Hoff DD, Li C-P, et al. Expanded analyses of NAPOLI-1: phase 3 study of MM-398 (nal-IRI), with or without 5-fluorouracil and leucovorin, versus 5-fluorouracil and leucovorin, in metastatic pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy. J Clin Oncol. 2015;33(suppl 3; abstr 234). doi: 10.1200/jco.2015.33.3_suppl.234.
6. Kindler HL, Hammel P, Reni M, et al. Olaparib as maintenance treatment following first-line platinum-based chemotherapy (PBC) in patients (pts) with a germline BRCA mutation and metastatic pancreatic cancer (mPC): phase III POLO trial. J Clin Oncol. 2019;37(suppl; abstr LBA4).
7. Golan T, Hammel P, Reni M, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. doi: 10.1056/NEJMoa1903387.