Andrea Wang-Gillam, MD, PhD, Clinical Director of the GI Oncology Program and Director of Developmental Therapeutics at Washington University in St. Louis, was the invited discussant of SEQUOIA and HALO 109-301. She tried to make sense of the two negative studies of pegylated agents in advanced pancreatic cancer.

Andrea Wang-Gillam, MD, PhD

For the SEQUOIA trial of pegylated interleukin-10 (IL-10), Dr. Wang-Gillam noted that pegilodecakin is but one of numerous cytokines now in development in cancer. “They are here to stay,” she said, but acknowledged that cytokines are “complex entities” that are not well understood. Early trials of pegilodecakin showed encouraging activity, but patient numbers were small. She said that moving from a phase I trial of 21 patients to a phase III trial of 566 patients required “a leap of faith,” and she questioned whether the early efficacy signal was strong enough to do so. “You really need robust phase II data with go/no-go signals before you jump to phase III.”

They called the result of SEQUOIA “humbling,” with a 6-month overall survival and 3-month progression-free survival. “Basically, 50% of patients fell off-study after the first [computed tomography] scan,” she said. It is doubtful, she added, that the lack of benefit was not due to pegilodecakin’s toxicity, as “minimum immune-related adverse events were noted.” She maintained, “Toxicity really had no impact on FOLFOX [fluourouracil, leucovorin, oxaliplatin] intensity and can’t be blamed for the lack of efficacy.”

Possible Reasons for Failure

It is possible that the dose of the drug was not adequate, since sustained high concentrations are necessary with IL-10. “It’s tricky to study cytokines: they can be bad or good, depending on the concentration or the context,” Dr. Wang-Gillam said. She also questioned whether the drug sufficiently boosted T cells and whether an increase in T cells in the tumor microenvironment is enough to impact clinical outcome.

Commenting next on PEGPH20, Dr. Wang-Gillam explained that this is a pegylated hyaluronidase that aims to dissolve hyaluronan, a major component of extracellular matrix in pancreatic cancer. In preclinical and early-phase studies, PEGPH20 “worked beautifully,” she said, improving median overall survival from 5.2 to 9.2 months in HALO-202.

“I thought a 4-month improvement in progression-free survival was pretty generous in a phase II study,” she said. “However, overall survival was not statistically significant.” Moreover, she continued, in the phase Ib/II SWOG S1313 trial, overall survival was actually worse with the addition of PEGPH20 to modified FOLFIRINOX (leucovorin, fluorouracil, irinotecan, oxaliplatin) in patients unselected by hyaluronan status.1 “So, there were concers about this drug…, but based on the data, a phase III trial was launched. We were hoping the trial would be positive, but overall survival was basically 11 months in each arm,” she said.

She noted that toxicity was manageable, dose intensity was comparable between the arms, and the hyaluronan threshold was consistent between phase II and phase III studies. The lack of difference with PEGPH20 might be explained by better standard-of-care treatment or better patient selection; perhaps the use of low–molecular-weight heparin in all patients actually had a survival effect, she said.

“Unfortunately, we have not had a good track record with stroma-depleting or -disrupting agents,” she continued. “HALO 109-301 raised questions on the validity of the stroma-disrupting approach.” She was hopeful that other means of targeting the tumor microenvironment may prove more effective, including focal adhesion kinase inhibitors, angiotensin inhibitors, vitamin D analogs, and combinatorial strategies. “But the tumor microenvironment is complex, dynamic, and heterogeneous,” she cautioned. “I have to say the story is not dead. We just need to understand more.”

DISCLOSURE: Dr. Wang-Gillam has served in a consulting or advisory role for Merck, Eisai, AstraZeneca, Bristol-Myers Squibb, Jacobio, Rupgene, and Tyme; and has received institutional research funding from AstraZeneca, BioMed Valley Discoveries, Boston Biomedical, Bristol-Myers Squibb, CTI, Gossamer, Hutchison MediPharma, Ipsen, Lilly, Merck, Newlink Genetics, Pfizer, Rafael Pharmaceuticals, Roche, Verastem, and Xcovery.

REFERENCE

1. Ramanathan RK, McDonough SL, Philip PA, et al: Phase Ib/II randomized study of FOLFIRINOX plus pegylated recombinant human hyaluronidase vs FOLFIRINOX alone in patients with metastatic pancreatic adenocarcinoma: SWOG S1313. J Clin Oncol 37:1062-1069, 2019.