The failure of Incyte's epacadostat last year cooled enthusiasm for cancer immunotherapies designed to build upon the strong foundation laid by the PD-(L)1 inhibitor class, now led by Merck & Co.'s Keytruda.
Yet early- and mid-stage work continues on agents that either block the defenses against immune response put up by tumor cells or stimulate the body's immune system to fight cancer. A recent count by the Cancer Research Institute, for example, found more than 1,700 combination studies involving PD-(L)1 blockers.
The upcoming meeting of the American Society for Clinical Oncology may see early and mid-stage data from agents working in a number of these pathways, called immune checkpoints for their ability to turn the body's natural defenses on or off. Because Keytruda, Bristol-Myers Squibb's Opdivo, Roche's Tecentriq and others are the standard of care in many cancer settings, many new immunotherapies ultimately will need to show they work in tandem with the PD-(L)1 antibodies. The following are a list of some of the novel pathways that should see some progress in the coming year.
Target: STING (stimulator of interferon gene complex)
Target: LAG-3 (lymphocyte activation gene-3)
Target: TIM-3 (T-cell immunoglobulin and mucin domain-3)
Top assets/companies: ADU-S100 from Aduro and Novartis; GSK3745417 from GlaxoSmithKline; MK-1454 from Merck & Co.
The Aduro and Merck candidates are limited by their need to be delivered through intratumoral injection, which means they could be used in melanoma, for example, but might not have much applicability in for cancers deep inside the body. MK-1454 data at the European Society for Medical Oncology (ESMO) meeting in 2018 showed signs of modest efficacy when combined with Keytruda. GSK3745417 can be delivered with intravenous infusions; so far, it is in an early dosing trial. Data from ADU-S100 plus spartalizumab will be featured at ASCO.
Top assets/companies: TSR-033 from GSK; REGN 3767 from Regeneron; BMS-986016 from Bristol-Myers; FS118 from F-Star
TSR-033 was one of several oncology assets GSK acquired when it bought Tesaro for $5.1 billion, so progress here would be most welcome. Regeneron and Bristol-Myers both will have posters at ASCO for their respective candidates in combination with their respective PD-1 inhibitors. F-Star's is a bispecific combining LAG-3 and PD-L1 inhibition; it had been subject to an option deal with Merck KGaA, but the German group has passed.
Top assets/companies: LY3321367 from Eli Lilly; BGB-A425 from BeiGene; SYM023 from Symphogen; MBG453 from Novartis.
A classic pairing with PD-(L)1. All of the above are in Phase 1 trials combined with each company's experimental PD-(L)1 compounds, as well as external, approved versions of the checkpoint inhibitor class. Lilly has presented early safety data showing a high level of antidrug antibody response, although that response did not affect pharmacokinetics, along with signs of tumor response. Little data has emerged from any of the other assets in this class.
Top assets/companies: Bintrafusp alfa from Merck KGaA and GSK (bispecific PD-L1); AVID200 from Forbius; Galunisertib from Eli Lilly; CART-PSMA-TGFβRD from the University of Pennsylvania.
Perhaps the biggest bet in all of oncology is Merck KGaA's decision to go head-to-head against Merck & Co in first-line non-small cell lung cancer. This trial hypothesizes that the bispecific bintrafusp alfa can block the PD-1 pathway as potently as Keytruda and that inhibiting TGF-beta will provide additive benefit by obstructing another mechanism tumors use to shut down immune response.
Lilly, meanwhile, has been testing galunisertib for several years, and reported some promising looking Phase 2 data in pancreatic cancer. TGF-beta also appears to be the only novel immune checkpoint on this list in which chimeric antigen receptor T-cells are thought to be a potential treatment technology, as the University of Pennsylvania has a trial underway in metastatic castrate-resistant prostate cancer.
Top assets/companies: PF-04518600 from Pfizer; BMS 986178 from Bristol-Myers; INCAGN1949 from Incyte.
These are in very early-stage human trials to test dose levels and measure biological response. Bristol-Myers' trial, which combined the OX40 with Opdivo and Yervoy (ipilimumab) found that the drug stimulated immune response. Pfizer's asset, sometimes called PF-8600, has achieved stable disease in some patients.