Therapy focus – pancreatic cancer developers press on, despite failures

Analysis

The word failure having become synonymous with pancreatic cancer drug development, it will be seen as ironic that the most important advance of recent years concerned the old chemotherapy regimen Folfirinox. That success, in the adjuvant setting, has already derailed one biopharma competitor – Targovax.

This week saw another fall by the wayside as Merrimack canned development of istiratumab after this bombed in a first-line study. Given all the disappointments it might come as a surprise that the industry’s mid-stage pancreatic cancer pipeline contains nearly 100 projects, including eight in phase III, with several readouts expected soon (see tables below).

Among the most keenly awaited readouts will be those testing the entry of immuno-oncology into this field, which is one in which anti-PD-(L)1 agents have yet to make their mark. Mid-stage studies of combinations comprising Merck & Co’s Keytruda or Bristol-Myers Squibb’s Opdivo in the second-line setting could yield data by the end of this year, for instance.

Also, Astrazeneca/Merck & Co’s Parp inhibitor, Lynparza, has a phase III readout in the maintenance setting after first-line chemo in germline BRCA-mutated disease. Lynparza will be trying to repeat yesterday’s success in the Solo-1 trial of first-line maintenance in ovarian cancer – clearly a less tough disease to treat.

Shifting standards

However, all players will be keeping an eye on Folfirinox. At this year’s Asco meeting Folfirinox was declared the likely new standard of care in adjuvant pancreatic cancer treatment after yielding median overall survival of four and a half years – 20 months longer than the current standard, Gemzar.

This claimed the scalp of Targovax’s vaccine TG01, as the company admitted that it meant that its study was using the wrong comparator, and that it could not afford to run the five-year clinical trial that would now be needed.

Folfirinox is already an option in first-line disease, and as yet there is no suggestion that it might outperform the entrenched front-line leaders, Gemzar and Celgene’s Abraxane. (Roche’s Tarceva is also approved first-line, but appears to be a less popular choice.)

However, the French Unicancer consortium is running a first-line treatment study called Neopan that pits Gemzar against Folfirinox and reads out in March 2019. Any suggestion that Folfininox is better than Gemzar would have serious repercussions on any front-line trial that gives comparator patients Gemzar.

And Folfirinox’s adjuvant success could already make for soul-searching among companies such as Fibrogen, whose pamrevlumab is being pitted against Gemzar and Abraxane in a neoadjuvant study. Leerink analysts reckon pamrevlumab’s future could hinge on the adoption of a new standard and how resectability is assessed; Fibrogen is to reveal its phase III design in August.

Selected upcoming pancreatic cancer trial readouts 
Project Company Design Line of therapy Status Primary completion Trial ID
BL-8040 +/- Keytruda Biolinerx/Merck & Co Single-arm (Keynote-202) 2nd-line Phase II Jun 2018 NCT02826486
CG200745 Crystalgenomics Combo with Gemzar + Tarceva; single-arm 1st-line Phase I/II Jul 2018 NCT02737228
PEGPH20 Halozyme Therapeutics Combo with Gemzar + Abraxane 1st-line Phase II Sep 2018 NCT01839487
Parvovirus H-1 Oryx Single-arm 2nd-line Phase I/II Sep 2018 NCT02653313
NANT Cancer Vaccine Nantkwest Combo with various agents 2nd-line Phase I/II Oct 2018 NCT03136406
NANT-008 Nantpharma Combo with chemo + Avastin 1st-line Phase I/II Oct 2018 NCT03127124
Opdivo +/- Yervoy Bristol-Myers Squibb Combo with radiation 2nd-line Phase II Nov 2018 NCT02866383
LOAd703 oncolytic virus Lokon Pharma Combo with Gemzar + Abraxane; single-arm 2nd-line Phase I/II Nov 2018 NCT02705196
Lynparza Astrazeneca/Merck & Co gBRCA mutated Maintenance after 1st-line chemo Phase III Nov 2018 NCT02184195
MK-0646 +/- Gemzar +/- Tarceva Merck & Co Versus Gemzar + Tarceva 2nd-line Phase I/II Nov 2018 NCT00769483
Pamrevlumab Fibrogen Combo with Gemzar + Abraxane Neoadjuvant Phase I/II Dec 2018 NCT02210559
Abemaciclib +/- LY3023414 Lilly Versus Gemzar or capecitabine 2nd-line Phase II Dec 2018 NCT02981342
AM0010 Lilly Combo with Folfox 2nd-line Phase III Jan 2019 NCT02923921
Gemzar Unicancer consortium Versus Folfirinox (Neopan study) 1st-line Phase III Mar 2019 NCT02539537
Abraxane Celgene Combo with Gemzar (Apact study) Adjuvant Phase III Apr 2019 NCT01964430
Glufosfamide Eleison Versus 5-FU 2nd-line Phase III Jun 2019 NCT01954992
Source: EvaluatePharma & Clinicaltrials.gov.

In first-line treatment it was in addition to Gemzar and Abraxane that istiratumab failed. This was despite Merrimack specifically recruiting patients with high serum levels of free IGF-1; a personalised approach is being taken by other groups, too, including Halozyme with PEGPH20 in the hotly awaited Halo-301 study.

Perhaps the most publicised phase III pancreatic cancer readout concerns Lilly's AM010, though this is in the second-line setting; it passed an interim futility analysis in March. This was originated by Armo, a young biotech recently bought out by Lilly for $1.6bn, and carries with it much of the sector’s hope for cytokines and related approaches.

Abraxane was developed by Abraxis Bioscience, a company founded by Patrick Soon-Shiong and sold to Celgene in 2010. It is not surprising to see Mr Soon-Shiong’s current biotech ventures such as Nantkwest and Nantpharma also active in the pancreatic cancer field.

Meanwhile, the long-awaited readout of glufosfamide, under development by the private company Eleison Pharmaceuticals, seems to have been delayed. The trial had been due to yield data a year ago, but now has a June 2019 completion date, having been expanded to include Chinese hospitals (Asco-GI – Pancreatic cancer field awaits sparse data, January 24, 2017).

If pancreatic cancer is already an extremely tough cancer to crack then shifting clinical standards could throw a fresh spanner in the works.

Selected industry assets in phase III pancreatic cancer trials 
Project Company Mechanism of action Trial ID
AM0010 (pegilodecakin) Lilly IL-10 receptor agonist NCT02923921 
Lynparza Astrazeneca/Merck & Co Parp inhibitor NCT02184195 
Masican (masitinib) AB Science CD117 inhibitor; FGFR3 inhibitor; PDGFR antagonist 20013-002293-41
Glufosfamide Elesion Alkylating agent NCT01954992 
Imbruvica Johnson & Johnson/Abbvie BTK inhibitor NCT02436668
Nanoplatin (demplatin pegraglumer) Orient Europharma/Nanocarrier Nanoparticle-bound chemo NCT02043288 
Napabucasin Sumitomo Dainippon Pharma NANOG inhibitor; STAT3 inhibitor; Wnt/beta-catenin signalling pathway inhibitor NCT02993731 
PEGPH20 (hyaluronidase) Halozyme Therapeutics Hyaluronan regulator NCT02715804 
Source: EvaluatePharma.

To contact the writer of this story email Jacob Plieth in London at jacobp@epvantage.com or follow @JacobPlieth on Twitter

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