Two novel treatments once thought to hold promise in the treatment of metastatic pancreatic cancer have not proved to be effective in phase III trials, investigators reported at the 2020 Gastrointestinal Cancers Symposium. When combined with standard chemotherapy, a pegylated form of human hyaluronidase (PEGPH20) as well as pegylated interleukin-10 (pegilodecakin)failed to meet their primary endpoint of overall survival.

“HALO 109-301 was a negative study with no improvement in overall survival or progression-free survival with the addition of pegylated recombinant human hyaluronidase (PEGPH20) to gemcitabine and albumin-bound nab-paclitaxel. A lack of benefit was observed in all subgroups,” announced Margaret Tempero, MD, FASCO, Professor of Medicine at the University of California, San Francisco (UCSF), and Director of the UCSF Pancreas Center.¹

Margaret Tempero, MD, FASCO

Johanna C. Bendell, MD

J. Randolph Hecht, MD

“In the SEQUOIA trial, combination therapy with FOLFOX (fluorouracil [5-FU]/leucovorin/oxaliplatin) and pegilodecakin did not improve overall survival, progression-free survival, or objective response rate in second-line pancreatic adenocarcinoma,” reported Johanna C. Bendell, MD, Director of the GI Cancer Research Program and Chief Development Officer of Sarah Cannon Research Institute, Nashville.²

Commenting on SEQUOIA in an interview with The ASCO Post, lead investigator J. Randolph Hecht, MD, said, “For 5 years, I’ve been involved in developing the pegilodecakin regimen and trial design, and I am disappointed about the results for this terrible disease.” He noted that SEQUOIA and HALO 109-301 join four other highly anticipated trials in pancreatic cancer that proved negative: APACT (adjuvant nab-paclitaxel plus gemcitabine), CanStem 111P (napabucasin), ­RESOLVE (ibrutinib plus nab-paclitaxel/gemcitabine), and a phase II trial of durvalumab plus tremelimumab.While PEGPH20 and pegilodecakin are both pegylated agents, Dr. Hecht suggested that pegylation was not the problem. More likely, “the problem was the targets: they were not the right targets or were insufficient by themselves.”  

HALO 109-301

HALO 109-301 was a randomized, double-blind, placebo-controlled, phase III trial of standard chemotherapy with or without PEGPH20 as first-line treatment in patients with metastatic pancreatic ductal adenocarcinoma and high expression of hyaluronan (50% by immunohistochemistry).¹ Hyaluronan is a major component of the desmoplasia observed in the tumor microenvironment in pancreatic cancer. This desmoplasia is associated with increased interstitial pressure, compression of the tumor vasculature, and impairment of the perfusion and delivery of drugs. PEGPH20 degrades hyaluronan, and in preclinical models, has shown improved delivery of drug and improved efficacy, Dr. Tempero said.

The HALO 109-301 trial was developed based on findings from a randomized phase II study in which patients with hyaluronan-high tumors treated with PEGPH20 plus gemcitabine and nab-paclitaxel experienced improved progression-free survival.³

Investigators used hyaluronan as a biomarker for tumor selection. They screened 2,799 patients from 244 sites in 22 countries, ultimately randomly assigning 494 patients with hyaluronan-high metastatic disease 2:1 to gemcitabine/nab-paclitaxel plus PEGPH20 or placebo. All patients received prophylaxis with enoxaparin to prevent venous and arterial thrombotic events and dexamethasone for muscle cramping. The primary endpoint was overall survival.

“For statistical planning, it was assumed that the median overall survival for the control arm would be approximately 8.5 months. The study was powered to detect a hazard ratio [HR] of 0.67 and a 50% increase in the median overall survival,” she said.

“For the primary endpoint, overall survival, there was no difference between the two arms,” Dr. Tempero reported, noting that the median overall survival of 11.5 months in the control arm was “much higher than anticipated.” Subsequent anticancer therapy was similar between the arms, and no subgroup was identified with an improved survival from PEGPH20. Median overall survival was 11.5 months in the control arm and 11.2 months in the PEGPH20 arm (P = .97), and median progression-free survival was 7.1 months in both groups (P = .97). There were slightly more objective responses in the PEGPH20 arm: 47% vs 36% with chemotherapy alone (HR = 1.29, 95% confidence interval = 1.03–1.63), with a complete response rate of 0.6% in each group. The number of cycles initiated and the duration of treatment, as well as the relative dose intensity, were similar in both arms.

Adverse events were more common in the PEGPH20 arm, consistent with the known safety profile of PEGPH20 in combination with chemotherapy, but they were not thought to have impacted the survival endpoint, she said. Based on these results, Halozyme has discontinued the development of this drug.

SEQUOIA Trial

SEQUOIA was a randomized phase III study of FOLFOX alone or with pegilodecakin (PEG–interleukin-10) in patients with pancreatic cancer refractory to a gemcitabine-based regimen. No differences were observed between the arms in the primary endpoint, overall survival.

“Pegilodecakin has multiple possible immune effects, including increasing T-cell clonality and reversing T-cell exhaustion,” said Dr. Hecht. “Unlike some putative immunotherapeutic agents, pegilodecakin has demonstrated single-agent responses, particularly in renal cell carcinoma and melanoma, whereas conventional checkpoint inhibitors have shown almost no activity in microsatellite-stable pancreatic cancer…. In single-arm cohorts in the phase I/Ib IVY trial (evaluating pegilodecakin monotherapy or with standard second-line FOLFOX), we observed much longer-than-expected clinical activity and overall survival for this poor-prognosis group.⁴ That led to the phase III SEQUOIA trial.”

SEQUOIA evaluated pegilodecakin plus FOLFOX as second-line treatment in 567 patients. The majority had previously received gemcitabine/nab-paclitaxel, but none had undergone surgery or radiotherapy. Patients were randomly assigned to FOLFOX alone or with pegilodecakin and could continue pegilodecakin after stopping FOLFOX. The primary endpoint was overall survival.

Median overall survival was 6.3 months with FOLFOX alone and 5.8 months with the addition of pegilodecakin (P = .06565); median progression-free survival was 2.1 months in each arm (P = .8144). Response rates were 5.6% and 4.6%, respectively, with no complete responses seen, Dr. Bendell reported.

Grade ≥ 3 adverse events were more common among patients receiving the pegilodecakin regimen, including thrombocytopenia, anemia, neutropenia, and fatigue. The safety profile was consistent with other studies of the drug.

“Although pegilodecakin was well tolerated, with short-lasting hematologic toxicities as seen in the phase Ib trial, unfortunately, there was no improvement in progression-free survival or overall survival,” Dr. Hecht said. “Correlative biomarker analysis is still pending, and trials in renal cell and lung carcinomas in combination with checkpoint inhibitors are ongoing. The immunotherapy of pancreatic cancer has been extraordinarily difficult and probably requires the combined use of agents that affect multiple pathways.”

He added, “On a side note, this trial is actually the largest done of FOLFOX in this setting. The overall survival of about 6 months is in line with a meta-analysis of oxaliplatin-based regimens documented in smaller studies⁵ and with the regimen of liposomal irinotecan/5-FU/leucovorin from the registrational NAPOLI-1 trial,⁶ indicating that it is a reasonable second-line regimen.” 

DISCLOSURE: The HALO 109-301 study was funded by Halozyme. SEQUOIA was funded by Eli Lilly and Company.
Dr. Tempero has received honoraria from Japan Pancreatic Society and Oregon Health & Science University; has served in a consulting or advisory role for AbbVie, Advance Medical Inc, Astellas Pharma, AstraZeneca, BioPharm Communications, Bristol-Myers Squibb, Celgene, CPRIT, EcoR1 Capital, Eisai, FibroGen, Halozyme, Ignyta, Immunovia, Merck, Pharmacyclics LLC, Pharmacyte Biotech, and Tocagen; has received institutional research funding from Celgene and Halozyme; and has been reimbursed for travel, accommodations, or other expenses by AbbVie, AstraZeneca, BioPharm Communications, Bristol-Myers Squibb, Celgene, CPRIT, Eisai, Halozyme, Pharmacyclics LLC, Pharmacyte Biotech, and Tocagen. Dr. Bendell has served in a consulting or advisory for Amgen, Apexigen, Arch Oncology, ARMO BioSciences, Array BioPharma, AstraZeneca, Bayer, Beigene, Bicycle Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Cerulean Pharma, Continuum Clinical, Cyteir, Daiichi Sankyo, EMD Serono, Evelo Therapeutics, Five Prime Therapeutics, FORMA Therapeutics, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, Incyte, Innate Pharma, Ipsen, Janssen, Kyn, Leap Therapeutics, Lilly, Macrogenics, MedImmune, Merck, Merrimack, Moderna Therapeutics, Molecular Partners, Novartis, Oncogenex, OncoMed, Phoenix Biotech, Prelude Therapeutics, Relay Therapeutics, Sanofi, Seattle Genetics, Taiho Pharmaceuticals, Tanabe Research, TD2, TG Therapeutics, Tizona Therapeutics Inc, Tolero Pharmaceuticals, and Torque; has received institutional research funding from Abbott/AbbVie, Acerta Pharma, ADC Therapeutics, Agios, Amgen, Apexigen, Arch Oncology, Arcus Biosciences, Array BioPharma, Arrys, AstraZeneca/MedImmune, ARMO BioSciences, Bayer, BeiGene, Bellicum, Bicycle Therapeutics, Blueprint Medicines, Boehringer Ingelheim, Boston Biomedical, Bristol-Myers Squibb, Calithera Biosciences, Celgene, Celldex, Cyteir, CytomX Therapeutics, Daiichi Sankyo, eFFECTOR Therapeutics, EMD Serono, Evelo Therapeutics, Five Prime Therapeutics, FORMA Therapeutics, Forty Seven, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, Gossamer Biopharma, Gritstone Oncology, Harpoon Therapeutics, ImClone Systems, Incyte, Innate Pharma, Ipsen, Jacobio, Janssen, Kolltan Pharmaceuticals, Leap Therapeutics, Lilly, Macrogenics, Marshall Edwards, Merck, Merrimack, Mersana, Merus, Millennium Pharmaceuticals, Molecular Partners, Nektar, Novartis, Novocure, Oncogenex, OncoMed, Onyx, Pfizer, Pieris Pharmaceuticals, Phoenix Biotech, Prelude Therapeutics, Revolution Medicines, Relay Therapeutics, Rgenix, Sanofi, Seattle Genetics, Shattuck Labs, Sierra Oncology, Sorrento Therapeutics, Stem CentRx, SynDevRx, Synthorx Inc, Taiho Pharmaceutical, Takeda, Tarveda Therapeutics, TempestTx, TG Therapeutics, Tizona Therapeutics Inc, Torque, TRACON Pharma, Tyrogenex, Unum Therapeutics, Vyriad, and Zymeworks; and has been reimbursed for travel, accommodations, or other expenses by ARMO BioSciences, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, FORMA Therapeutics, Gilead Sciences, Ipsen, Lilly, MedImmune, Merck, Novartis, OncoMed, Roche/Genentech, and Taiho Pharmaceutical. Dr. Hecht has received honoraria from ARMO BioSciences, AstraZeneca, Bristol-Myers Squibb, Gritstone, Halozyme, Ipsen, Merck, and Roche; has received institutional research funding from AbbVie, Advaxis, Amgen, ARMO BioSciences, Astellas Pharma, Forty Seven, Halozyme, Immunomedics, Lilly, Merck, and Novartis; and has been reimbursed for travel, accommodations, or other expenses by Advaxis and Lilly.

REFERENCES

1. Tempero MA, et al: HALO 109-301: A randomized, double-blind, placebo-controlled, phase III study of pegvorhyaluronidase alfa (PEGPH20) + nab-paclitaxel/gemcitabine in patients with previously untreated hyaluronan-high metastatic pancreatic ductal adenocarcinoma. 2020 Gastrointestinal Cancers Symposium. Abstract 638. Presented January 24, 2020.

2. Hecht JR, et al: Randomized phase III study of ­FOLFOX alone and with pegilodecakin as second-line therapy in patients with metastatic pancreatic cancer (SEQUOIA). 2020 Gastrointestinal Cancers Symposium. Abstract 637. Presented January 24, 2020.

3. Hingorani SR, et al: HALO 202: Randomized phase II study of PEGPH20 plus nab-paclitaxel/gemcitabine vs nab-paclitaxel/gemcitabine in patients with untreated, metastatic pancreatic ductal adenocarcinoma. J Clin Oncol 36:359-366, 2018.

4. Hecht JR, et al: Overall survival of PEGylated pegilodecakin with 5-FU/LV and oxaliplatin (FOLFOX) in metastatic pancreatic adenocarcinoma. 2018 ASCO Annual Meeting. Abstract 4119. Presented June 3, 2018.

5. Wainberg ZA, et al: Meta-analysis of OS for pancreatic cancer patients receiving 5FU and oxaliplatin-based therapy after failing first-line gemcitabine-containing therapy. 2019 Gastrointestinal Cancers Symposium. Abstract 202. Presented January 18, 2019.

6. Wang-Gillam A, et al: NAPOLI-1 phase III study of liposomal irinotecan in metastatic pancreatic cancer. Eur J Cancer 108:78-87, 2019.