The pancreatic cancer pipeline lost Threshold Pharmaceuticals’ evofosfamide and OncoMed Pharmaceuticals’ tarextumab in recent weeks, but 2016 should nevertheless be an important year for the indication with four phase III trials due to read out, with careful patient selection a growing theme.
Ten pivotal phase III studies with eight agents are under way in this notoriously intractable cancer. Those due to render results this year include the Pillar and Impress studies of NewLink Genetics’ cancer vaccine, algenpantucel-L, and the Pancrit-1 study of Immunomedics’ radiolabelled MUC-1 antibody yttrium Y-90 clivatuzumab tetraxetan (see table below).
However, the first trial to report data will be the Janus-1 study of Incyte’s Jakafi, pencilled in for April. This is the first of two pancreatic cancer studies with the Jak 1/2 inhibitor, the other being Janus-2, which is due to report mid-2017.
Expectations for both of these trials are modest at best, especially given the recent termination of a phase II study in metastatic colorectal cancer for lack of efficacy (Incyte falls victim to the biotech bear market, January 28, 2016).
Both Janus studies selectively enrol patients with high levels of C-reactive protein (CRP), a biomarker of inflammation, as this was the subgroup in which Jakafi showed efficacy in the earlier phase II Recap trial in pancreatic cancer. This had tested Jakafi second line and showed patients with high CRP to have a 53% reduction in risk of death, with a p value of 0.01.
This makes the studies some of the first in pancreatic cancer to attempt to select patients based on a biomarker. The highly heterogeneous nature of the disease might be responsible for the failure of most chemotherapeutics so far, and identifying subgroups with biological characteristics amenable to targeted therapies could eventually mirror lung and breast cancers.
AstraZeneca’s phase III study of Lynparza is also testing a patient-selection approach. The trial enrols patients with gBRCA mutations whose disease has not progressed on first-line platinum chemo. Evidence from breast and ovarian cancers suggests that BRCA-mutant cancers are highly sensitive to PARP inhibitors and platinum-based agents. Lynparza is already approved for ovarian cancer.
The Lynparza study is not due to report until 2017. Other agents with 2017 pivotal readouts are Eleison Pharmaceuticals’ glufosfamide, Orient Pharma’s NC-6004, a novel micellar formulation of cisplatin, and Gilead’s Jak inhibitor momelotinib.
AB Science appears to be conducting a study to validate an undisclosed biomarker that it retrospectively identified in a failed phase III trial with mastitinib, though few details have been revealed – hence this is excluded from this analysis.
|Jakafi||Incyte||Janus-1||318||Capcitabine +/- ruxolitinib||Second line||NCT02119663||Apr 2016|
|Algenpantucel-L||NewLink Genetics||Impress||722||Gem +/- algenpantucel-L||Resected, adjuvant||NCT01072981||Jun 2016|
|Algenpantucel-L||NewLink Genetics||Pillar||302||Folfox/Folfirinox +/- algenpantucel-L||First line, partially resected||NCT01836432||Dec 2016|
|Y-90 clivatuzumab||Immunomedics||Pancrit-1||440||Low-dose gem +/- Y-90 clivatuzumab||Third line or later||NCT01956812||Dec 2016|
|Glufosfamide||Eleison||–||480||Glufosfamide vs 5FU||Second line||NCT01954992||May 2017|
|Nanoplatin/NC-6004||Orient/Nanocarrier||–||290||Gemcitabine +/- NC-6004||First line||NCT02043288||Jun 2017|
|Jakafi||Incyte||Janus-2||290||Ruloxitinib vs placebo||Second line||NCT02117479||Jun 2017|
|Lynparza||AstraZeneca||–||145||Lynparza vs placebo||First-line maintenance||NCT02184195||Oct 2017|
|Momelotinib||Gilead Sciences||–||430||Gem/Abraxane +/- momelotinib||First line||NCT02101021||Dec 2017|
|Imbruvica||AbbVie/J&J||Resolve||326||Gem/Abraxane +/- Imbruvica||First line||NCT02436668||Mar 2018|
|Phase II (selected)|
|PEGPH20||Halozyme||–||237||Gem/Abraxane +/- PEGPH20||First line||NCT01839487||Apr 2016|
|Necuparanib||Momenta||–||180||Gem/Abraxane +/- necuparanib||First line||NCT01621243||Dec 2016|
|Demcizumab||OncoMed||Yosemite||201||Gem/Abraxane +/-demcizumab||First line||NCT02289898||2017|
|Acalabrutinib||Acerta/AstraZeneca||–||120||Gem/Abraxane +/- acalabrutinib||First line||NCT02570711||Dec 2017|
If any of the 2016-17 pivotal studies are successful, evolving standards might still make it difficult to draw conclusions from across-trial comparisons, particularly in the second-line setting, where there is no consensus.
This could change, of course, if Merrimack’s Onivyde becomes the new standard after the Napoli-1 study established a benefit for Onivyde against 5FU/leucovorin alone – though physicians can only speculate how much benefit the new liposomal irinotecan conferred over the native molecule, which is used in a currently-used combination, Folfiri.
Recent analysis of Napoli-1 looked at CA19-9, and established that the benefit correlates with baseline CA19-9 levels, something that might become a useful biomarker.
EP Vantage has identified a number of registration phase II programmes, all in the first-line setting, two of which are due to render results this year: Halozyme’s PEGPH20 and Momenta’s necuparanib. Halozyme is notable for also using a biomarker approach, and it also plans a phase III study in high-HA patients later this year.
Given that pancreatic cancer has historically proven to be so intractable it would be easy to dismiss hopes for positive results in the upcoming pivotal readouts. However, there is a sufficiently large number over the coming year to give grounds for some cautious optimism.
This story has been corrected to reflect the status of Incyte and NewLink projects.